AU749992B2 - Method of designing agonists and antagonists to IGF receptor - Google Patents

Description

WO 99/28347 PCT/AU98/00998 METHOD OF DESIGNING AGONISTS AND ANTAGONISTS TO IGF RECEPTOR Field of the Invention This invention relates to the field of receptor structure and receptor/ligand interactions. In particular it relates to the field of using receptor structure to predict the structure of related receptors and to the use of the determined structures and predicted structures to select and screen for agonists and antagonists of the polypeptide ligands.

Background of the Invention Insulin is the peptide hormone that regulates glucose uptake and metabolism. The two types of diabetes mellitus are associated either with an inability to produce insulin because of destruction of the pancreatic islet cells (Homo-Delarche, F. Boitard, C.,1996, Immunol. Today 10: 456-460) or with poor glucose metabolism resulting from either insulin resistance at the target tissues, or from inadequate insulin secretion by the islets or faulty liver function (Taylor, S. et al., 1994, Diabetes, 43: 735-740).

Insulin-like growth factors-1 and 2 (IGF-1 and 2) are structurally related to insulin, but are more important in tissue growth and development than in metabolism. They are primarily produced in the liver in response to growth hormone, but are also produced in most other tissues, where they function as paracrine/autocrine regulators. The IGFs are strong mitogens, and are involved in numerous physiological states and certain cancers (Baserga, 1996, TibTech 14: 150-152).

Epidermal growth factor (EGF) is a small polypeptide cytokine that is unrelated to the insulin/IGF family. It stimulates marked proliferation of epithelial tissues, and is a member of a larger family of structurally-related cytokines, such as transforming growth factor a, amphiregulin, betacellulin, heparin-binding EGF and some viral gene products. Abnormal EGF family signalling is a characteristic of certain cancers (Soler, C. Carpenter, G., 1994 In Nicola, N. (ed) Guidebook to Cytokines and Their receptors", Oxford Univ. Press, Oxford, ppl94-197; Walker, F. Burgess, A. 1994, In Nicola, N. (ed) Guidebook to Cytokines and Their receptors", Oxford Univ. Press, Oxford, pp198-201).

Each of these growth factors mediates its biological actions through binding to the corresponding receptor. The IR, IGF-1R and the insulin receptor-related receptor (IRR), for which the ligand is not known, are closely related to each other, and are referred to as the insulin receptor subfamily. A WO 99/28347 PCT/AU98/00998 2 large body of information is now available concerning the primary structure of these insulin receptor subfamily members (Ebina, et al., 1985 Cell 747-758; Ullrich, et al., 1985, Nature 313: 756-761; Ullrich, A. et al., 1986, EMIBO J 5: 2503-2512; Shier, P. Watt, V. 1989, J. Biol. Chem. 264: 14605-14608) and the identification of some of their functional domains (for reviews see De Meyts, P. 1994, Diabetologia 37: 135-148; Lee, J. Pilch, P.

F. 1994 Amer. J. Physiol. 266: C319-C334.; Schaffer, L. 1994, Eur. J. Biochem.

221: 1127-1132). IGF-1R, IR and IRR are members of the tyrosine kinase receptor superfamily and are closely related to the epidermal growth factor receptor (EGFR) subfamily, with which they share significant sequence identity in the extracellular region as well as in the cytoplasmic kinase domains (Ullrich, A. et al., 1984 Nature 309: 418-425; Ward, C. W. et al., 1995 Proteins: Structure Function Genetics 22: 141-153). Both the insulin and EGF receptor subfamilies have a similar arrangement of two homologous domains (L1 and L2) separated by a cys-rich region of approximately 160 amino acids containing 22-24 cys residues (Bajaj, et al., 1987 Biochim.

Biophys. Acta 916: 220-226; Ward, C. W. et al., 1995 Proteins: Structure Function Genetics 22: 141-153). The C-terminal portion of the IGF-1R ectodomain (residues 463 to 906) is comprised of four domains: a connecting domain, two fibronectin type 3 (Fn3) repeats, and an insert domain (O'Bryan, J. et al., 1991 Mol Cell Biol 11: 5016-5031). The C-terminal portion of the EGFR ectodomain (residues 477-621) consists solely of a second cys-rich region containing 20 cys residues (Ullrich, A. et al., 1984, Nature 309: 418- 425).

Little is known about the secondary, tertiary and quaternary structure of the ectodomains of these receptor subfamilies. Unlike the members of the EGFR subfamily which are transmembrane monomers which dimerise on binding ligand, the IR subfamily members are homodimers, held together by disulphide bonds. The extracellular region of the IR/IGF-1R/IRR monomers contains an a-chain 703 to 735 amino acid residues) and 192-196 residues of the i-chain. There is a -23 residue transmembrane segment, followed by the cytoplasmic portion (354 to 408 amino acids), which contains the catalytic tyrosine kinase domain flanked by juxtamembrane and C-tail regulatory regions and is responsible for mediating all receptor-specific functions (White, M. F. Kahn, C. R. 1994 J. Biol. Chem. 269: Chemical analyses of the receptor suggest that the a-chains are linked to the if-chains WO 99/28347 PCT/AU98/00998 3 via a single disulphide bond, with the IR dimer being formed by at least two a-a disulphide linkages (Finn, F. et al., 1990, Proc. Natl. Acad. Sci. 87: 419-423; Chiacchia, K. 1991, Biochem. Biophys. Res. Commun. 176, 1178- 1182; Schaffer, L. Ljungqvist, 1992, Biochem. Biophys. Res. Comm. 189: 650-653; Sparrow, L. et al., 1997, J. Biol. Chem. 47: 29460-29467).

Although the three-dimensional (3D) structures of the ligands EGF, TGF-alpha (Hommel, et al., 1992, J. Mol. Biol. 227:271-282), insulin (Dodson, E. et al., 1983, Biopolymers 22:281-291), IGF-1 (Sato, et al., 1993, Int J Peptide Protein Res 41:433-440) and IGF-2 (Torres, A. et al.,1995, J. Mol. Biol. 248:385-401) are known, and numerous analytical and functional studies of ligand binding to EGFR (Soler, C. Carpenter, 1994 In Nicola (ed) Guidebook to Cytokines and Their receptors", Oxford Univ.

Press, Oxford, pp194-197), IGF-1R and IR (see De Meyts, 1994 Diabetologia, 37:135-148) have been carried out, the mechanisms of ligand binding and subsequent transmembrane signalling have not been resolved.

Ligand-induced, receptor-mediated phosphorylation is the signalling mechanism by which most cytokines, polypeptide hormones and membraneanchored ligands exert their biological effects. The primary kinase may be part of the intracellular portion of the transmembrane receptor protein, as in the tyrosine kinase receptors (for review see Yarden, et al., 1988, Ann.

Rev. Biochem. 57:443-478) or the Ser/Thr kinase receptors (Alevizopoulos,

A.

Mermod, 1997, BioEssays, 19:581-591) or may be non-covalently associated with the cytoplasmic tail of the transmembrane protein(s) making up the receptor complex, as in the case of the haemopoietic growth factor receptors (Stahl, et al., 1995, Science 267:1349-1353). The end result is the same, ligand binding leads to receptor dimerization or oligomerization or a conformational change in pre-existing receptor dimers or oligomers, resulting in activation by transphosphorylation, of the covalently attached or non-covalently associated protein kinase domains (Hunter, 1995, Cell, 80:225-236).

Many oncogenes have been shown to be homologous to growth factors, growth factor receptors or molecules in the signal transduction pathways (Baserga, R.,1994 Cell, 79:927-930; Hunter, 1997 Cell, 88:333- 346). One of the best examples is v-Erb (related to the EGFR). Since overexpression of a number of growth factor receptors results in liganddependent transformation, an alternate strategy for oncogenes is to regulate WO 99/28347 PCT/AU98/00998 4 the expression of growth factor receptors or their ligands or to directly bind to the receptors to stimulate the same effect (Baserga, 1994 Cell, 79:927- 930). Examples are v-Src, which activates IGF-1 R intracellularly; c-Myb, which transforms cells by enhancing the expression of IGF1R; and SV40 T antigen which interacts with the IGF-1R and enhances the secretion of IGF-1 (see Baserga, R.,1994 Cell, 79:927-930 for review). Cells in which the IGF-1R has been disrupted or deleted cannot be transformed by SV40 T antigen. If oncogenes activate growth factors and their receptors; then tumour suppressor genes should have the opposite effect. One good example of this is the Wilm's tumour suppressor gene, WT1, which suppresses the expression of IGF-1R (Drummond, J. et al., 1992, Science, 257:275-277). Cells that are driven to proliferate by oncogenes undergo massive apoptosis when growth factor receptors are ablated, since, unlike normal cells, they appear unable to withdraw from the cell-cycle and enter into the Go phase (Baserga, R.,1994 Cell, 79:927-930).

The insulin-like growth factor-1 receptor (IGF-1R) is one of several growth-factor receptors that regulate the proliferation of mammalian cells.

However, its ubiquitousness and certain unique aspects of its function make IGF-1R an ideal target for specific therapeutic interventions against abnormal growth, with very little effect on normal cells (see Baserga, 1996 TIBTECH, 14:150-152). The receptor is activated by IGF1, IGF2 and insulin, and plays a major role in cellular proliferation in at least three ways: it is essential for optimal growth of cells in vitro and in vivo; several cell types require IGF-1R to maintain the transformed state; and activated IGF-1R has a protective effect against apoptotic cell death (Baserga, 1996 TIBTECH, 14:150-152). These properties alone make it an ideal target for therapeutic interventions. Transgenic experiments have shown that IGF-1R is not an absolute requirement for cell growth, but is essential for the establishment of the transformed state (Baserga, R.,1994 Cell, 79: 927-930). In several cases (human glioblastoma, human melanoma; human breast carcinoma; human.

lung carcinoma; human ovarian carcinoma; human rhabdomyosarcoma; mouse melanoma, mouse leukaemia; rat glioblastoma; rat rhabdomyosarcoma; hamster mesothelioma the transformed phenotype can be reversed by decreasing the expression of IGF-1R using antisense to IGF-1R (Baserga, 1996 TIBTECH 14:150-152); or by interfering with its function by antibodies to IGF-1R (human breast carcinoma; human WO 99/28347 PCT/AU98/00998 rhabdomyosarcoma) or by dominant negatives of IGF-1R (rat glioblastoma; Baserga, R.,1996 TIBTECH 14:150-152).

Three effects are observed when the function of IGF-1R is impaired: tumour cells undergo massive apoptosis which results in inhibition of tumourogenesis; surviving tumour cells are eliminated by a specific immune response; and such a host response can cause a regression of an established wild-type tumour (Resnicoff, et al., 1995, Cancer Res. 54:2218-2222).

These effects, plus the fact that interference with IGF-1R function has a limited effect on normal cells (partial inhibition of growth without apoptosis) makes IGF-1R a unique target for therapeutic interventions (Baserga, 1996 TIBTECH 14:150-152). In addition IGF-1R is downstream of many other growth factor receptors, which makes it an even more generalised target. The implication of these findings is that if the number of IGF-1Rs on cells can be decreased or their function antagonised, then tumours cease to grow and can be removed immunologically. These studies establish that IGF-1R antagonists will be extremely important therapeutically.

Many cancer cells have constitutively active EGFR (Sandgreen, E. P., et al., 1990, Cell, 61:1121-135; Karnes, W. E. et al., 1992, Gastroenterology, 102:474-485) or other EGFR family members (Hines, N. E.,1993, Semin.

Cancer Biol. 4:19-26). Elevated levels of activated EGFR occur in bladder, breast, lung and brain tumours (Harris, A. et al., 1989, In Furth Greaves (eds) The Molecular Diagnostics of human cancer. Cold Spring Harbor Lab.

Press, CSH, NY, pp353-357). Antibodies to EGFR can inhibit ligand activation of EGFR (Sato, J. et al., 1983 Mol. Biol. Med. 1:511-529) and the growth of many epithelial cell lines (Aboud-Pirak et al., 1988, J. Natl Cancer Inst.

85:1327-1331). Patients receiving repeated doses of a humanised chimeric anti-EGFR monoclonal antibody showed signs of disease stabilization. The large doses required and the cost of production of humanised monoclonal antibody is likely to limit the application of this type of therapy. These findings indicate that the development of EGF antagonists will be attractive anticancer agents.

Summary of the Invention The present inventors have now obtained 3D structural information concerning the insulin-like growth factor receptor (IGF-1R). This information can be used to predict the structure of related members of the insulin WO 99/28347 PCT/AU98/00998 6 receptor family and provides a rational basis for the development of ligands for specific therapeutic applications.

Accordingly, in a first aspect the present invention provides a method of designing a compound able to bind to a molecule of the insulin receptor family and to modulate an activity mediated by the molecule, including the step of assessing the stereochemical complementarity between the compound and the receptor site of the molecule, wherein the receptor site includes: amino acids 1 to 462 of the receptor for IGF-1, having the atomic coordinates substantially as shown in Figure 1; a subset of said amino acids, or; amino acids present in the amino acid sequence of a member of the insulin receptor family, which form an equivalent three-dimensional structure to that of the receptor molecule as depicted in Figure 1.

The phrase "insulin receptor family" encompasses, for example, IGF- 1R, IR and IRR. In general, insulin receptor family members show similar domain arrangements and share significant sequence identity (preferably at least 40% identity).

By "stereochemical complementarity" we mean that the biologically active substance or a portion thereof correlates, in the manner of the classic "lock-and-key" visualisation of ligand-receptor interaction, with the groove in the receptor site.

In a preferred embodiment of this aspect of the invention, the compound is selected or modified from a known compound identified from a database.

In a further preferred embodiment, the compound is designed so as to complement the structure of the receptor molecule as depicted in Figure 1.

In a further preferred embodiment, the compound has structural regions able to make close contact with amino acid residues at the surface of the receptor site lining the groove, as depicted in Figure 2.

In a further preferred embodiment, the compound has a stereochemistry such that it can interact with both the L1 and L2 domains of the receptor site.

In a further preferred embodiment, the compound has a stereochemistry such that it can interact with the L1 domain of a first monomer of the receptor homodimer, and with the L2 domain of the other monomer of the receptor homodimer.

In a further preferred embodiment, the interaction of the compound with the receptor site alters the position of at least one of the L1, L2 or cysteine- WO 99/28347 PCT/AU98/00998 7 rich domains of the receptor molecule relative to the position of at least one of the other of said domains. Preferably, the compound interacts with the P sheet of the L1 domain of the receptor molecule, thereby causing an alteration in the position of the L1 domain relative to the position of the cysteine-rich domain or of the L2 domain. Alternatively, the compound interacts with the receptor site in the region of the interface between the L1 domain an the cysteine-rich domain of the receptor molecule, thereby causing the L1 domain and the cysteine-rich domain to move away from each other. In another preferred embodiment, the compound interacts with the hinge region between the L2 domain and the cysteine-rich domain of the receptor molecule, thereby causing an alteration in the positions of the L2 domain and the cysteine-rich domain relative to each other.

In a further preferred embodiment, the stereochemical complementarity between the compound and the receptor site is such that the compound has a Kb for the receptor side of less than 10GM, more preferably is less than 10- 8

M.

In a further preferred embodiment or the first aspect of the present invention, the compound has the ability to increase an activity mediated by the receptor molecule.

In a further preferred embodiment, the compound has the ability to decrease an activity mediated by the receptor molecule. Preferably, the stereochemical interaction between the compound and the receptor site is adapted to prevent the binding of a natural ligand of the receptor molecule to the receptor site. It is preferred that the compound has a K, of less than 10-M, more preferably less than 10 8 M and more preferably less than 10 9

M.

In a further preferred embodiment of the first aspect of the present invention, the receptor is the IGF-1R, or the insulin receptor.

In a second aspect, the present invention provides a computer-assisted method for identifying potential compounds able to bind to a molecule of the insulin receptor family and to modulate an activity mediated by the molecule, using a programmed computer including a processor, an input device, and an output device, including the steps of: inputting into the programmed computer, through the input device, data comprising the atomic coordinates of the IGF-1R molecule as shown in Figure i, or a subset thereof; generating, using computer methods, a set of atomic coordinates of a structure that possesses stereochemical complementarity to the atomic WO 99/28347 PCT/AU98/00998 8 coordinates of the IGF-1R site as shown in Figure 1, or a subset thereof, thereby generating a criteria data set; comparing, using the processor, the criteria data set to a computer database of chemical structures; selecting from the database, using computer methods, chemical structures which are structurally similar to a portion of said criteria data set; and outputting, to the output device, the selected chemical structures which are similar to a portion of the criteria data set.

In a preferred embodiment of the second aspect, the programmed computer includes a data storage system which includes the dtatbase of chemical structures.

In a preferred embodiment of the second aspect, the method is used to identify potential compounds which have the ability to decrease an activity mediated by the receptor.

In another preferred embodiment, the computer-assisted method further includes the step of selecting one or more chemical structures from step (e) which interact with the receptor site of the molecule in a manner which prevents the binding of natural ligands to the receptor site.

In another preferred embodiment, the computer-assisted method further includes the step of obtaining a compound with a chemical structure selected in steps and and testing the compound for the ability to decrease an activity mediated by the receptor.

In a further preferred embodiment, the computer-assisted method is used to identify potential compounds which have the ability to increase an activity mediated by the receptor molecule.

In another preferred embodiment, the computer-assisted method further includes the step of obtaining a molecule with a chemical structure selected in steps and and testing the compound for the ability to increase an activity mediated by the receptor.

In a further preferred embodiment of the second aspect of the present invention, the receptor is the IGF-1R, or the insulin receptor.

In a third aspect, the present invention provides a method of screening of a putative compound having the ability to modulate the activity of a receptor of the insulin receptor family, including the steps of identifying a putative compound by a method according to the first or second aspects, and testing the WO 99/28347 PCT/AU98/00998 9 compound for the ability to increase or decrease an activity mediated by the receptor.

In a preferred embodiment of the third aspect, the test is carried out in vitro.

In a further preferred embodiment of the third aspect, the test is a high throughput assay.

In a preferred embodiment of the third aspect, the test is carried out in vivo.

Brief Description of the Drawings Figure 1. IGF-1R residues 1-462, in terms of atomic coordinates refined to a resolution of 2.6 A (average accuracy 0.3A). The coordinates are in relation to a Cartesian system of orthogonal axes.

Figure 2. Depiction of the residues lining the groove of the IGF-1R receptor fragment 1-462.

Figure 3. Gel filtration chromatography of affinity-purified IGF-1R/462 protein. The protein was purified on a Superdex S200 column (Pharmacia) fitted to a BioLogic L.C. system (Biorad), equilibrated and eluted at 0.8 ml/min with 40 mMvl Tris/150 mM NaCl/0.02% NaN3 adjusted to pH Protein eluting in peak 1 contained aggregated IGF-1R/462 protein, peak 2 contained monomeric protein and peak 3 contained the c-myc undecapeptide used for elution from the Mab 9E10 immunoaffinity column. Nonreduced SDS-PAGE of fraction 2 from IGF-1R/462 obtained following Superdex S200 (Fig.la). Standard proteins are indicated.

Figure 4. Ion exchange chromatography of affinity-purified, truncated IGF- 1R ectodomain. A mixture of gradient and isocratic elution chromatography was performed on a Resource Q column (Pharmacia) fitted to a BioLogic System (Biorad), using 20 mM Tris/pH 8.0 as buffer A and the same buffer containing 1M NaCI as buffer B. Protein solution in TBSA was diluted at least 1:2 with water and loaded onto the column at 2 ml/min. Elution was monitored by absorbance (280 nm) and conductivity (mS/cm). Target protein (peak 2) eluted isocratically with 20 mM Tris/0.14 M NaC1 pH 8.0. Inset: WO 99/28347 PCT/AU98/00998 Isoelectric focusing gel (pH 3 7; Novex Australia Pty Ltd)of fraction 2. The pi was estimated at 5.1 from standard proteins (not shown).

Figure 5. Polypeptide fold for residues 1-462 of IGF-1R. The L1 domain is at the top, viewed from the N-terminal end and L2 is at the bottom. The space at the centre is of sufficient size to accommodate IGF-1. Helices are indicated by curled ribbon and b-strands by arrows. Cysteine side chains are drawn as ball-and-stick with lines showing disulfide bonds. The arrow points in the direction of view for L1 in Figure 7.

Figure 6. Amino acid sequences of IGF-1R and related proteins, a, L1 and L2 domains of human IGF-1R and IR are shown based on a sequence alignment for the two proteins and a structural alignment for the L1 and L2domains.

Positions showing conservation physico-chemical properties of amino acids are boxed, residues used in the structural alignment are shown in Times Italic and residues which form the Trp 176 pocket are in Times Bold.

Secondary structure elements for L1 (above the sequences) and L2 (below) are indicated as cylinders for helices and arrows for p-strands. Strands are shaded (pale, medium and dark grey) according to the p-sheet to which they belong. Disulfide bonds are also indicated. b, Cys-rich domains of human IGF-1R, IR and EGFR (domains 2 and 4) are aligned based on sequence and structural considerations. Secondary structural elements and disulfide bonds are indicated above the sequences. The dashed bond is only present in IR.

Different types of disulfide bonded modules are labelled below the sequences as open, filled or broken lines. Boxed residues show conservation of physicochemical properties and structurally conserved residues for modules 4-7 are shown in Times Italic. Residues from EGFR which do not conform to the pattern are in lowercase with probable disulfide bonding indicated below and the conserved Trp 176 and the semi-conserved Gln 182 are in Times Bold.

Figure 7. Stereo view of a superposition of the L1 (white) and L2 (black) domains. Residues numbers above are for L1 and below for L2. The side chain of Trp 176 which protrudes into the core of L1 is drawn as ball-andstick.

WO 99/28347 PCT/AU98/00998 11 Figure 8. Schematic diagram showing the association of three P-finger motifs. p-strands are drawn as arrows and disulfide bonds as zigzags.

Figure 9: Sequence alignment of hIGF-1R, hIR and hIRR ectodomains, derived by use of the PileUp program in the software package of the Genetics Computer Group, 575 Science Drive, Madison, Wisconsin, USA.

For assignment of homologous 3D structures see Figure 6.

Figure 10 Gel filtration chromatography of insulin receptor ectodomain and MFab complexes. hIR -11 ectodomain dimer (5 20 mg) was complexed with MFab derivatives (15-25 mg each) of the anti-hIR antibodies 18-44, 83-7 and 83-14 (Soos et al., 1986). Flution profiles were generated from samples loaded on to a Superdex S200 column (Pharmacia), connected to a BioLogic chromatography system (Biorad) and monitored at 280 nm. The column was eluted at 0.8 ml/min with 40 mM Tris/150 mM sodium chloride/0.02% sodium azide buffer adjusted to pH 8.0: Profile 0, hIR -11 ectodomain, Profile 1, ectodomain mixed with MFab 18-44; Profile 2 ectodomain mixed with MIFab18-44 and MFab 83-14; Profile 3, ectodomain mixed with MFab 18-44, MFab 83-14 and MFab 83-7. The apparent mass of each complex was determined from a plot of the following standard proteins: thyroglobulin (660 kDa), ferritin (440 kDa), bovine gamma globulin (158 kDa), bovine serum albumin (67 kDa), chicken ovalbumin (44 kDa) and equine myoglobin (17 kDa).

Figure 11 Schematic representations of electron microscopy images of the hIR ectodomain dimer.

Detailed Description of the Invention We describe herein the expression, purification, and crystallization of a recombinant truncated IGF-1R fragment (residues 1-462) containing the L1cysteine-rich-L2 region of the ectodomain. The selected truncation position is just downstream of the exon 6/exon 7 junction (Abbott, A. et al., 1992. J Biol Chem., 267:10759-10763), and occurs at a position where the sequences of the IR and EGFR families diverge markedly (Ward, C. et al.,1995, Proteins: Struct., Funct., Genet. 22:141-153; Lax, et al., 1988, Molec.

Cellul. Biol. 8:1970-1978) suggesting it represents a domain boundary. To WO 99/28347 PCT/AU98/00998 12 limit the effects of glycosylation, the IGF-1R fragment was expressed in Lec8 cells, a glycosylation mutant of Chinese hamster ovary (CHO) cells, whose defined glycosylation defect produces N-linked oligosaccharides truncated at N-acetyl glucosamine residues distal to mannose residues (Stanley, P. 1989, Molec. Cellul. Biol. 9:377-383). Such an approach has facilitated glycoprotein crystallization (Davis, S. et al., 1993, Protein Eng. 6:229-232; Liu, et al., 1996, J. Biol. Chem. 271:33639-33646).

The IGF-1R construct described herein includes a c-myc peptide tag (Hoogenboom, H. et al.,1991, Nucleic Acids Res. 19:4133-4137) that is recognised by the Mab 9E10 (Evan, G. et al., 1985, Mol. Cell. Biol. 5:3610- 3616) enabling the expressed product to be purified by peptide elution from an antibody affinity column followed by gel filtration over Superdex S200.

The purified proteins crystallized under a sparse matrix screen (Jancarik, J. Kim, 1991, J. Appl. Cryst. 24:409-411) but the crystals were of variable quality, with the best diffracting to 3.0-3.5A. Isocratic gradient elution by anion-exchange chromatography yielded protein that was less heterogenous and gave crystals of sufficient quality to determine the structure of the first three domains of the human IGF-1R.

The IGF-1R fragment consisted of residues 1-462 of IGF-1R linked via an enterokinase-cleavable pentapeptide sequence to an eleven residue c-myc peptide tag at the C-terminal end. The fragment was expressed in Lec8 cells by continuous media perfusion in a bioreactor using porous carrier disks. It was secreted into the culture medium and purified by peptide elution from an anti-c-myc antibody column followed by Superdex S200 gel filtration. The receptor fragment bound two anti-IGF-1R monoclonal antibodies, 24-31 and 24-60, which recognize conformational epitopes, but could not be shown to bind IGF-1 or IGF-2. Crystals of variable quality were grown as rhombic prisms in 1.7 M ammonium sulfate at pH 7.5 with the best diffracting to A. Further purification by isocratic elution on an anion-exchange column gave protein which produced better quality crystals, diffracting to 2.6 A, that were suitable for X-ray structure determination.

The structure of this fragment (IGF-1R residues 1-462; L1-cys rich-L2 domains) has been determined to 2.6 A resolution by X-ray diffraction. The L domains each adopt a compact shape consisting of a single stranded righthanded P-helix. The cys-rich region is composed of eight disulphide-bonded modules, seven of which form a rod-shaped domain with modules associated WO 99/28347 PCT/AU98/00998 13 in a novel manner. At the centre of this reasonably extended structure is a space, bounded by all three domains, and of sufficient size to accommodate a ligand molecule. Functional studies on IGF-1R and other members of the insulin receptor family show that the regions primarily responsible for hormone-binding map to this central site. Thus this structure gives a first view of how members of the insulin receptor family might interact with their ligands.

Another group has reported the crystallization of a related receptor, the EGFR, in a complex with its ligand EGF (Weber, et al., 1994, J Chromat. 679:181-189). However, difficulties were encountered with these crystals which diffracted to only 6 A, insufficient for the determination of an atomic resolution structure of this complex (Weber, et al., 1994, J Chromat 679:181-189) or the generation of accurate models of structurally related receptor domains such as IGF-1R and IR by homology modelling.

The present inventors have developed 3D structural information about cytokine receptors in order to enable a more accurate understanding of how the binding of ligand leads to signal transduction. Such information provides a rational basis for the development of ligands for specific therapeutic applications, something that heretofore could not have been predicted de novo from available sequence data.

The precise mechanisms underlying the binding of agonists and antagonists to the IGF-1R site are not fully clarified. However, the binding of ligands to the receptor site, preferably with an affinity in the order of 1O-M or higher, is understood to arise from enhanced stereochemical complementarity relative to naturally occurring IGF-1 ligands.

Such stereochemical complementarity, pursuant to the present invention, is characteristic of a molecule that matches intra-site surface residues lining the groove of the receptor site as eneumerated by the coordinates set out in Figure 1. The residues lining the groove are depicted in Figure 2. By "match" we mean that the identified portions interact with the surface residues, for example, via hydrogen bonding or by enthalpyreducing Van der Waals interactions which promote desolvation of the biologically active substance within the site, in such a way that retention of the biologically active substance within the groove is favoured energetically.

Substances which are complemetary to the shape of the receptor site characterised by amino acids positioned at atomic coordinates set out in WO 99/28347 PCT/AU98/00998 14 Figure 1 may be able to bind to the receptor site and, when the binding is sufficiently strong, substantially prohibit binding of the naturally occurring ligands to the site.

It will be appreciated that it is not necessary that the complementarity between ligands and the receptor site extend over all residues lining the groove in order to inhibit binding of the natural ligand.

Accordingly, agonists or antagonists which bind to a portion of the residues lining the groove are encompassed by the present invention.

In general, the design of a molecule possessing stereochemical complementarity call be accomplished by means of techniques that optimize, either chemically or geometrically, the "fit" between a molecule and a target receptor. Known techniques of this sort are reviewed by Sheridan and Venkataraghavan, Acc. Chem Res. 1987 20 322; Goodford, J. Med. Chem.

1984 27 557; Beddell, Chem. Soc. Reviews 1985, 279; Hol, Angew. Chem.

1986 25 767 and Verlinde C.L.M.J Hol, W.G.J. Structure 1994, 2, 577, the respective contents of which are hereby incorporated by reference. See also Blundell et al., Nature 1987 326 347 (drug development based on information regarding receptor structure).

Thus, there are two preferred approaches to designing a molecule, according to the present invention, that complements the shape of IGF-1R or a related receptor molecule. By the geometric approach, the number of internal degrees of freedom (and the corresponding local minima in the molecular conformation space) is reduced by considering only the geometric (hard-sphere) interactions of two rigid bodies, where one body (the active site) contains "pockets" or "grooves" that form binding sites for the second body (the complementing molecule, as ligand). The second preferred approach entails an assessment of the interaction of respective chemical groups ("probes") with the active site at sample positions within and around the site, resulting in an array of energy values from which three-dimensional contour surfaces at selected energy levels can be generated.

The geometric approach is illustrated by Kuntz et al., J. Mol. Biol.

1982 161 269, the contents of which are hereby incorporated by reference, whose algorithm for ligand design is implemented in a commercial software package distributed by the Regents of the University of California and further described in a document, provided by the distributor, which is entitled "Overview of the DOCK Package, Version the contents of which are WO 99/28347 PCT/AU98/00998 hereby incorporated by reference. Pursuant to the Kuntz algorithm, the shape of the cavity represented by the IGF-R1 site is defined as a series of overlapping spheres of different radii. One or more extant data bases of crystallographic data, such as the Cambridge Structural Database System maintained by Cambridge University (University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, and the Protein Data Bank maintained by Brookhaven National Laboratory (Chemistry Dept. Upton, NY 11973, is then searched for molecules which approximate the shape thus defined.

Molecules identified in this way, on the basis of geometric parameters, can then be modified to satisfy criteria associated with chemical complementarity, such as hydrogen bonding, ionic interactions and Van der Waals interactions.

The chemical-probe approach to ligand design is described, for example, by Goodford, J. Med. Chem. 1985 28 849, the contents of which are hereby incorporated by reference, and is implemented in several commercial software packages, such as GRID (product of Molecular Discovery Ltd., West Way House, Elms Parade, Oxford OX2 9LL, Pursuant to this approach, the chemical prerequisites for a site-complementing molecule are identified at the outset, by probing the active site (as represented via the atomic coordinates shown in Fig. 1) with different chemical probes, water, a methyl group, an amine nitrogen, a carboxyl oxygen, and a hydroxyl.

Favored sites for interaction between the active site and each probe are thus determined, and from the resulting three-dimensional pattern of such sites a putative complementary molecule can be generated.

The chemical-probe approach is especially useful in defining variants of a molecule known to bind the target receptor. Accordingly, crystallographic analysis of IGF-1 bound to the receptor site is expected to provide useful information regarding the interaction between the archetype ligand and the active site of interest.

Programs suitable for searching three-dimensional databases to identify molecules bearing a desired pharmacophore include: MACCS-3D and ISIS/3D (Molecular Design Ltd., San Leandro, CA), ChemDBS-3D (Chemical Design Ltd., Oxford, and Sybyl/3DB Unity (Tripos Associates, St.

Louis, MO).

WO 99/28347 PCT/AU98/00998 16 Programs suitable for pharmacophore selection and design include: DISCO (Abbott Laboratories, Abbott Park, IL), Catalyst (Bio-CAD Corp., Mountain View, CA), and ChemDBS-3D (Chemical Design Ltd., Oxford, Databases of chemical structures are available from a number of sources including Cambridge Crystallographic Data Centre (Cambridge, U.K.) and Chemical Abstracts Service (Columbus, OH).

De novo design programs include Ludi (Biosym Technologies Inc., San Diego, CA), Sybyl (Tripos Associates) and Aladdin (Daylight Chemical Information Systems, Irvine, CA).

Those skilled in the art will recognize that the design of a mimetic may require slight structural alteration or adjustment of a chemical structure designed or identified using the methods of the invention.

The invention may be implemented in hardware or software, or a combination of both. However, preferably, the invention is implemented in computer programs executing on programmable computers each comprising a processor, a data storage system (including volatile and non-volatile memory and/or storage elements), at least one input device, and at least one output device. Program code is applied to input data to perform the functions described above and generate output information. The output information is applied to one or more output devices, in known fashion. The computer may be, for example, a personal computer, microcomputer, or workstation of conventional design.

Each program is preferably implemented in a high level procedural or object-oriented programming language to communicate with a computer system. However, the programs can be implemented in assembly or machine language, if desired. In any case, the language may be compiled or interpreted language.

Each such computer program is preferably stored on a storage medium or device ROIMI or magnetic diskette) readable by a general or special purpose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform the procedures described herein. The inventive system may also be considered to be implemented as a computer-readable storage medium, configured with a computer program, where the storage medium so WO 99/28347 PCT/AU98/00998 17 configured causes a computer to operate in a specific and predefined manner to perform the functions described herein.

Compounds designed according to the methods of the present invention may be assessed by a number of in vitro and in vivo assays of hormone function. For example, the identification of IGF-1R antagonists of may be undertaken using a solid-phase receptor binding assay. Potential antagonists may be screened for their ability to inhibit the binding of europium-labelled IGF ligands to soluble, recombinant IGF-1R in a microplate-based format. Europium is a lanthanide fluorophore, the presence of which can be measured using time-resolved fluorometry. The sensitivity of this assay matches that achieved by radioisotopes, measurement is rapid and is performed in a microplate format to allow high-sample throughput, and the approach is gaining wide acceptance as the method of choice in the development of screens for receptor agonists/antagonists see Apell et.al. J.

Biomolec. Screening 3:19-27, 1998 Inglese et. al. Biochemistry 37:2372- 2377, 1998).

Binding affinity and inhibitor potency may be measured for candidate inhibitors using biosensor technology.

The IGF-1R antagonists may be tested for their ability to modulate receptor activity using a cell-based assay incorporating a stably transfected, IGF-1-responsive reporter gene [Souriau, Fort, Roux, Hartley, O., LeFranc, M-P. and Weill, 1997, Nucleic Acids Res. 25, 1585-1590]. An IGF-1-responsive, luciferase reporter gene has been assembled and transfected in 293 cells. The assay addresses the ability of IGF-1 to activate the reporter gene in the presence of novel ligands. It offers a rapid (results within 6-8 hours of hormone exposure), high-throughput (assay can be conducted in a 96-well format for automated counting) analysis using an extremely sensitive detection system (chemiluminescence). Once candidate compounds have been identified, their ability to antagonise signal transduction via the IGF-1R can be assessed using a number of routine in vitro cellular assays such as inhibition of IGF-1-mediated cell proliferation, induction of apoptosis in the presence of IGF-1 and the ablation of IGF-1driven anchorage-independent cell growth in soft agar [D'Ambrosio, C., Ferber, Resnicoff, M. and Baserga, 1996, Cancer Res. 56, 4013-4020].

Such assays may be conducted on the P6 cell line, a cell line highly responsive to IGF as a result of the constitutive overexpression of the IGF-1R WO 99/28347 PCT/AU98/00998 18 (45-50,000 receptors/cell, [Pietrzkowski, Sell, Lammers, Ullrich, A.

and Baserga, R.,1992, Cell Growth.Diff. 3, 199-205]). Ultimately, the efficacy of any antagonist as a tumour therapeutic may be tested in vivo in animals bearing tumour isografts and xenografts as described [Resnicoff, Burgaud, Rotman, H. Abraham, D. and Baserga, 1995, Cancer Res. 55, 3739- 3741; Resnicoff, Sell, Rubini, Coppola, Ambrose, Baserga, R. and Rubin, 1994 Cancer Res. 54: 2218-2222].

Tumour growth inhibition assays may be designed around a nude mouse xenograft model using a range of cell lines. The effects of the receptor antagonists and inhibitors may be tested on the growth of subcutaneous tumours.

A further use of the structure of the IGF-1R fragment described here is in facilitating structure determination of a related protein, such as a larger fragment of this receptor, another member of the insulin receptor family or a member of the EGF receptor family. This new structure may be either of the protein alone, or in complex with its ligand. For crystallographic analysis this is achieved using the method of molecular replacement (Brunger, Meth.

Enzym. 1997 276 558-580, Navaza and Saludjian, ibid. 581-594, Tong and Rossmann, ibid. 594-611, Bentley, ibid. 611-619) in a program such as XPLOR. In this procedure diffraction data is collected from a crystalline protein of unknown structure. A transform of these data (Patterson function) is compared with a Patterson function calculated from a known structure.

Firstly, the one Patterson function is rotated on the other to determine the correct orientation of the unknown molecule in the crystal. The translation function is then calculated to determine the location of the molecule with respect to the crystal axes. Once the molecule has been correctly positioned in the unit cell initial phases for the experimental data may be calculated.

These phases are necessary for calculation of an electron density map from which structural differences may be observed and for refinement of the structure. Due to limitations in the method the search molecule must be structurally related to that which is to be determined. However it is sufficient for only part of the unknown structure 50%) to be similar to the search molecule. Thus the three dimensional structure of IGF-1R residues 1-462 may be used to solve structures consisting of related receptors, enabling a program of drug design as outlined above.

In summary, the general principles of receptor-based drug design can be applied by persons skilled in the art, using the crystallographic results presented above, to produce ligands of IGF-1R or other related receptors, having sufficient stereochemical complementarity to exhibit high affinity binding to the receptor site.

The present invention is further described below with reference to the following, non-limiting examples.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.

EXAMPLE 1 Expression, Purification and Crystallization of the IGF-1R Fragment.

Several factors hamper macromolecular crystallization including sample selection, purity, stability, solubility (McPherson, et al., 1995, Structure 3:759-768); Gilliland, G. Ladner, J. 1996, Curr. Opin.

.i .:Struct. Biol. 6:595-603), and the nature and extent of glycosylation (Davis, S.

et al., 1993, Protein Eng. 6:229-232). Initial attempts to obtain structural data from soluble IGF-1R ectodomain (residues 1-906) protein, expressed in Lec8 cells (Stanley, P. 1989, Molec. Cellul. Biol. 9:377-383) and purified by 30 affinity chromatography, produced large, well-formed crystals (1.0 mm x 0.2 O* mm x 0.2 mm) which gave no discernible X-ray diffraction pattern (unpublished data). Similar difficulties have been encountered with crystals of the structurally-related epidermal growth factor receptor (EGFR) ectodomain, which diffracted to only 6 A, insufficient for the determination of an atomic resolution structure (Weber, W. et al., 1994, J Chromat 679:181- 19A 189). This prompted us to search for a fragment of IGF-1R that was more amenable to X-ray crystallographic studies.

The fragment expressed (residues 1-462) comprises the Ll-cysteinerich-L2 region of the ectodomain. The selected truncation position at Val462 is four residues downstream of the exon 6/exon 7 junction (Abbott, A. et al., 1992, J Biol Chem. 267:10759-10763), and occurs at a position where the sequences of the IR and the structurally related EGFR families diverge markedly (Lax, et al., 1988, Molec Cell Biol. 8:1970-1978; Ward, C. et al., 1995, Proteins: Struct., Funct., Genet. 22:141-153), suggesting that it represents a domain boundary. The expression strategy included use of the pEE14 vector (Bebbington, C. R. Hentschel, C. C. 1987, In: Glover, D.

ed. DNA Cloning. Academic Press, San Diego. Vol 3, p163) in glycosidase-defective Lec8 cells (Stanley, 1989, Molec. Cellul. Biol. 9:377- *o* o.

••go• WO 99/28347 PCT/AU98/00998 383), which produce N-linked oligosaccharides lacking the terminal galactose and N-acetylneuraminic acid residues (Davis, S. et al., 1993, Protein Eng.

6:229-232; Liu, et al., 1996, J Biol Chem 271:33639-33646.). The construct contained a C-terminal c-myc affinity tag (Hoogenboom, H. et al., 1991, Nucl Acids Res. 19:4133-4137), which facilitated immunoaffinity purification by specific peptide elution and avoided aggressive purification conditions.

These procedures yielded protein which readily crystallized after a further gel filtration purification step. This provided a general protocol to enhance crystallisation prospects for labile, multidomain glycoproteins.

The structure of this fragment is of considerable interest, since it contains the major determinants governing insulin and IGF-1 binding specificity (Gustafson, T. A. Rutter, W. 1990, J. Biol. Chem. 265:18663- 18667; Andersen, A. et al., 1990, Biochemistry, 29:7363-7366; Schumacher, et al., 1991, J. Biol. Chem. 266:19288-19295; Schumacher, et al., 1993, J. Biol. Chem. 268:1087-1094; Schaffer, et al., 1993, J. Biol.

Chem. 268:3044-3047; Williams, P. et al., 1995, J. Biol. Chem. 270:3012- 3016), and is very similar to an IGF-1R fragment (residues 1-486) reported to act as a strong dominant negative for several growth functions and which induces apoptosis of tumour cells in vivo (D'Ambrosio, et al., 1996, Cancer Res. 56:4013-4020).

The expression plasmid pEE14/IGF-1R/462 was constructed by inserting the oligonucleotide cassette: AatlI 5'GACGTC GACGATGACGATAAG GAACAAAAACTCATC D V D D D D K E Q K L I (EK cleavage) (c-myc tail) S E E D L N (Stop) TCAGAAGAGGATCTGAAT TAGAATTC GACGTC 3' EcoRI AatlI encoding an enterokinase cleavage site, c-myc epitope tag (Hoogenboom, H.

et al., 1991, Nucleic acids Res. 19:4133-4137) and stop codon into the AatII site (within codon 462) of Igf-lr cDNA in the mammalian expression vector pECE (Ebina, et al., 1985, Cell, 40:747-758; kindly supplied by W. J.

Rutter, UCSF, USA), and introducing the DNA comprising the 5' 1521 bp of WO 99/28347 PCT/AU98/00998 21 the cDNA (Ullrich, et al., 1986, EMBO J. 5:2503-2512) ligated to the oligonucleotide cassette into the EcoRI site of the mammalian plasmid expression vector pEE14 (Bebbington, C. R. Hentschel, C. C. 1987, In: Glover, D. ed. DNA Cloning. Academic Press, San Diego. Vol 3, p163; Celltech Ltd., UK). Plasmid pEE14/IGF-1R/462 was transfected into Lec8 mutant CHO cells (Stanley, P. 1989, Molec. Cellul. Biol. 9:377-383) obtained from the American Tissue Culture Collection (CRL:1737), using Lipofectin (Gibco-BRL). Cell lines were maintained after transfection in glutamine-free medium (Glascow modification of Eagle's medium (GMEM; ICN Biomedicals, Australia) and 10% dialysed FCS (Sigma, Australia) containing 25 tM methionine sulphoximine (MSX; Sigma, Australia) as described (Bebbington, C. R. Hentschel, C. C. 1987, In: Glover, D. ed. DNA Cloning.

Academic Press, San Diego. Vol 3, p163). Transfectants were screened for protein expression by Western blotting and sandwich enzyme-linked immunosorbent assay (ELISA) (Cosgrove, et al., 1995, using monoclonal antibody (Mab) 9E10 (Evan et al., 1985) as the capture antibody, and either biotinylated anti-IGF-1R Mab 24-60 or 24-31 for detection(Soos et al., 1992; gifts from Ken Siddle, University of Cambridge, UK). Large-scale cultivation of selected clones expressing IGF-1R/462 was carried out in a Celligen Plus bioreactor (New Brunswick Scientific, USA) containing 70 g Fibra-Cel Disks (Sterilin, UK) as carriers in a 1.25 L working volume. Continuous perfusion culture using GMEM medium supplemented with non-essential amino acids, nucleosides, 25 pM MSX and 10% FCS was maintained for 1 to 2 weeks followed by the more enriched DMEM/F12 without glutamine, with the same supplemention for the next 4-5 weeks. The fermentation production run was carried out three times under similar conditions, and resulted in an estimated overall yield of 50 mg of receptor protein from 430 L of harvested medium.

Cell growth was poor during the initial stages of the fermentation when GMEM medium was employed, but improved dramatically following the switch to the more enriched medium. Target protein productivity was essentially constant during the period from -100 to 700 h of the 760 h fermentation, as measured by ELISA using Mab 9E10 as the capture antibody and biotinylated Mab 24-31 as the developing antibody.

Soluble IGF-1R/462 protein was recovered from harvested fermentation medium by affinity chromatography on columns prepared by coupling Mab 9E10 to divinyl sulphone-activated agarose beads (Mini Leak; WO 99/28347 PCT/AU98/00998 22 Kem EnTec, Denmark) as recommended by the manufacturer. Mini-Leak Low and Medium affinity columns with antibody loadings of 1.5-4.5 mg/ml of hydrated matrix were obtained, with the loading range of 2.5-3 mg/ml giving optimal performance (data not shown). Mab 9E10 was produced by growing hybridoma cells (American Tissue Culture Collection) in serum-free medium in the Celligen Plus bioreactor and recovering the secreted antibody (4 g) using protein A glass beads (Prosep-A, Bioprocessing Limited, USA).

Harvested culture medium containing IGF-1R/462 protein was adjusted to pH with Tris-HCl (Sigma), made 0.02% in sodium azide and passed at 3-5 ml/min over 50 ml Mab 9E10 antibody columns at 4° C. Bound protein was recovered by recycling a solution of 2-10 mg of the undecamer c-myc peptide EQKLISEEDLN (Hoogenboom et al., 1991) in 20 ml of Tris-buffered saline containing 0.02% sodium azide (TBSA). Between 65% and 75% of the product was recovered from the medium as estimated by ELISA, with a further 15-25% being recovered by a second pass over the columns. Peptide recirculation (-10 times) through the column eluted bound protein more efficiently than a single, slower elution. Residual bound protein was eluted with sodium citrate buffer at pH 3.0 into 1 M Tris HCl pH 8.0 to neutralize the eluant, and columns were re-equilibrated with TBSA.

Gel filtration over Superdex S200 (Pharmacia, Sweden), of affinitypurified material showed a dominant protein peak at -63 kDa, together with a smaller quantity of aggregated protein (Figure 3a). The peak protein migrated primarily as two closely spaced bands on reduced sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE; Figure 3b), reacted positively in the ELISA with both Mab 24-60 and Mab 24-31, and gave a single sequence corresponding to the N-terminal 14 residues of IGF-1R. No binding of IGF-1 or IGF-2 could be detected in the solid plate binding assay (Cosgrove et al., 1995, Protein Express Purif. 6:789-798). The IGF-1R/462 fragment was further purified by ion-exchange chromatography on Resource Q (Pharmacia, Sweden). Using shallow salt gradients, protein enriched in the slowest migrating SDS-PAGE band was obtained (data not shown), which formed relatively large, well-formed crystals (see below). Isoelectric focussing showed the presence of one major and two minor isoforms. Protein purified on Resource Q with an isocratic elution step of 0.14 M NaCl in mMl TrisCl at pH 8.0 (fraction 2, Figure 4) showed less heterogeneity on isoelectric focussing (Figure 4 inset) and SDS-PAGE (data not shown), and WO 99/28347 PCT/AU98/00998 23 produced crystals of sufficient quality for structure determination (see below).

Crystals were grown by the hanging drop vapour diffusion method using purified protein concentrated in Centricon 10 concentrators (Amicon Inc, USA) to 5-10 mg/ml in 10-20 mM Tris-HCl pH 8.0 and 0.02% (w/v) sodium azide, or 100 mM ammonium sulfate and 0.02% sodium azide.

Crystallization conditions were initially identified using the factorial screen (Jancarik, J. Kim, S.-H.,1991, J Appl Cryst 24:409-411),and then optimised.

Crystals were examined on an M18XHF rotating anode generator (Siemens, Germany) equipped with Franks mirrors (MSC, USA) and RAXIS IIC and IV image plate detectors (Rigaku, Japan).

From the initial crystallization screen of this protein, crystals of about 0.1 mm in size grew in one week. Upon refining conditions, crystals of up to 0.6 x 0.4 x 0.4 mm could be grown from a solution of 1.7-2.0 M ammonium sulfate, 0.1 M HEPES pH 7.5. The crystals varied considerably in shape and diffraction quality, growing predominantly as rhombic prisms with a length to width ratio of up to 5:1, but sometimes as rhombic bipyramids, the latter form being favoured when using material which had been eluted from the Mab 9E10 column at pH 3.0. Each crystal showed a minor imperfection in the form of very faint lines from the centre to the vertices.

Protein from dissolved crystals did not appear to be different from the protein stock solution when run on an isoelectric focusing gel. Upon X-ray examination, the crystals diffracted to 3.0-4.0 A and were found to belong to the space group P2 1 2 2 2 with a 76.8 A, b 99.0 A, c 119.6 A. In the diffraction pattern, the crystal variability noted above was manifest as a large and anisotropic mosaic spread, with concomitant variation in resolution. To improve the quality of the crystals, they were grown in the presence of various additives or wvere recrystallized. These methods failed to substantially improve the crystal quality although bigger crystals were obtained by recrystallization. The variability in crystal quality appeared to be due to protein heterogeneity, as demonstrated by the observation that more highly purified protein, eluted isocratically from the Resource Q column and showing one major band on isoelectric focusing (Figure 4 inset), produced crystals of sufficient quality for structure determination. These crystals diffracted to 2.6 A resolution with cell dimensions, a 77.0 A, b 99.5 A, c 120.1 A and mosaic spread of 0.50. Heavy metal derivatives of the IGF- WO 99/28347 PCT/AU98/00998 24 1R/462 crystals have been obtained and are leading to the determination of an atomic resolution structure of this fragment, which contains the L1, cysteine-rich and L2 domains of human IGF-1R.

EXAMPLE 2 Structure of the IGF-1R/1-462 Crystals were cryo-cooled to-170°C in a mother liquor containing glycerol, 2.2 M ammonium sulfate and 100 mM Tris at pH 8.0. Native and derivative diffraction data were recorded on Rigaku RAXIS IIc or IV area detectors using copper Kc radiation from a Siemens rotating anode generator with Yale/MSC mirroroptics. The space group was P2,2 1 2 1 with a 77.39 A, b 99.72 A, and c 120.29 A. Data were reduced using DENZO and SCALEPACK (Otwinowski, Z. Minor, 1996, Mode.Meth. Enzym.

276:307-326). Diffraction was notably anisotropic for all crystals examined.

Phasing by multiple isomorphous replacement(MIR) was performed with PROTEIN (Steigeman, W. Dissertation (Technical Univ. Munich, 1974) using anomalous scattering for both U02 and PIP derivatives. Statistics for data collection and phasing are given in Table 1. In the initial MIR map regions of protein and solvent could clearly be seen, but the path of the polypeptide was by no means obvious. That map was subject to solvent flattening and histogram matching in DM (Cowtan, K.,1994, Joint CCP4 and ESF-EACBM newslett. Protein Crystallogr. 31:34-38). The structure was traced and rebuilt using O (Jones, T. et al., 1991, Acta Crystallogr.

A47:110-119) and refined with X-PLOR 3.851 (Brunger, A. 1996, X-PLOR ReferenceManual 3.851, Yale Univ., New Haven, CT). After 5 rounds of rebuilding and energy minimisation the R-factor dropped to 0.279 and Rfree 0.359 for data 7-2.6 A resolution. The current model contains 458 amino acids and 3 N-linked carbohydrates but no solvent molecules. For residues with B(Ca) 70, A atomic positions are less reliable (37-42, 155-159, 305, 336-341, 404-406,453-458). There is weak electron density for residues 459- 461, but the c-myc tail appears completely disordered.

The 1-462 fragment consists of the N-terminal three domains of IGF- 1R (L1, cys-rich, L2), and contains regions of the molecule which dictate ligand specificity (17-23). The molecule adopts a reasonably extended structure (approximately 40 x 48 x 105 A) with domain 2 (cys-rich region) WO 99/28347 PCT/AU98/00998 making contact along the length of domain 1 (Ll) but very little contact with the third domain (L2) (see Figure This leaves a space at the centre of the molecule of approximately 24 A x 24 A x 24 A which is bounded on three sides by the three domains of the molecule. The space is of sufficient size to accommodate the ligand, IGF-1.

Table 1 Summary of Crystallographic data Data set" Resol. Mean R,,,,rgb Completeness No. of RIL.i,c Phasing FOMe I/s (multiplicity) sites powerd Native 2.6 18.7 0.064 0.996 0.47/0.71 PIP 3.0 15.8 0.060 0.982 3 0.66 1.71 U02Ac2 4.5 7.5 0.095 0.989 2 0.82 1.17 Refinement No of refl. No. of Atoms Ry.t Rree f Bonds' Anglesg resolution (free) (A) 7.0-2.6 24270 3903 0.237 0.304 0.017 0.048 (2693) a PIP, Di-4-iodobis(ethylenediamine)diplatinum dinitrate; UO2Ac2, Uranyl acetate.

b Rmerge ZhZj Ilh,j-Ihl ZhZj Ih. where Ih,j is an intensity measurement j and Ih is the mean intensity for that reflection h.

c Rcullis h I IFPI-I-Fp IF-icalcl I/Zhl IFplI-II-FpI where FpH, Fp and FHcalc are, respectively, derivative, native and heavy atom structure factors for centric reflections h.

d Phasing power 7h FI-calc /Zhc, where FHcalc is defined above and e is the lack of closure.

e FOM(figure of merit) <cos(Aoh)>, where Ac(h is the error in the phase angle for reflection h. Values are given before and after density modification at 3.0 and 2.8 A resolution, respectively.

f Rcrvst and Rfree are defined in Brunger, A.T. XPLOR reference manual 3.851 (Yale Univ., New Haven, CT, 1996) WO 99/28347 PCT/AU98/00998 26 g r.m.s. deviation from ideal bond and angle-related distances.

The L domains Each of the L domains (residues 1-150 and300-460) adopts a compact shape (24 x 32 x 37 A) consisting of a single-stranded right handed 0-helix and capped on the ends by short a-helices and disulfide bonds. The body of the domain looks like a loaf of bread, with the base formed from a flat sixstranded p-sheet, 5 residues long and the sides being p-sheets three residues long (Figures 5 The top is irregular, but in places is similar for the two domains. The two domains are superposable with an rms deviation in Co positions of 1.6 A for 109 atoms (Figure Although this fold is reminiscent of other P-helix proteins it is much simpler and smaller with very few elaborations, and thus it represents a new superfamily of domains. One notable difference between the two domains is that the indole ring of Trp 176 from the cys-rich region (Figure 6b) is inserted into the hydrophobic core of L1, and the C-terminal helix is only vestigial (Figure For the insulin receptor family the sequence motif of residues which form the Trp pocket in L1 does not occur in L2 (Figure 6a). However in the EGF receptor, which has an additional cys-rich region after the L2 domain (14, 15), the pocket motif can be found in both L domains and the Trp is conserved in both cys-rich regions (Figure 6b).

The repetitive nature of the P-helix is reflected in the sequence and the first five turns were correctly identified by Bajaj, et al. (1987, Biochim.Biophys. Acta 916:220-226), the conserved Gly residues being found in turns making one bottom edge of the domain. However, their conclusions about the fold were incorrect. The"helix-like" repeat is actually a pair of bends at the top edge of the domain. In their Motif V, the Gly is not in a bend but is followed by the insertion of a conserved loop of 7-8 residues (see Figure 6a). Glycine is structurally important in the Gly bends as mutation of these residues compromises folding of the receptor [van der Vorm, et al., 1992, J. Biol. Chem. 267, 66-71; Wertheimer, E. et al., 1994, J. Biol. Chem.

269, 7587-7592].

Comparison of the L domains with other right-handed P-helix structures such as pectate lyase (Yoder, M. et al., 1993,.Structure, 1:241- 251-1507) and the p22 tailspike protein (Steinbacher, et al., 1997, J.Mol.

Biol. 267:865-880) shows some striking similarities as well as differences. In WO 99/28347 PCT/AU98/00998 27 all cases the ends of the domain are capped by a-helices, but the L domains also have a disulphide bond at each end to hold the termini. The other 3helix domains are considerably longer and have significant twist to their sheets, while the L domains have flat sheets. Although the sizes of the helix repeats are similar (here 24-25 residues vs 22-23 for pectate lyase) the crosssections are quite different. The L domains have a rectangular cross-section, while pectate lyase and p22 tailspike protein are V-shaped, and have many, and sometimes quite large, insertions (Yoder, M. et al., 1993, Structure, 1:241-251-1507; Steinbacher, et al., 1997, J.Mol. Biol. 267:865-880). In the hydrophobic core a common feature is the stacking of aliphatic residues from successive turns of the P-helix, and near the C-terminus of each L domain there is also a short Asn ladder, reminiscent of the long Asn ladder observed in pectate lyase (Yoder, M. et al., 1993, Structure 1:241-251- 1507). On the opposite side of the L domains the Gly bend, as well as the two bends and sheet preceding it, have no counterpart in the other P-helix domains. Thus although the L domains are built on similar principles to the other P-helix domains they constitute a separate superfamily.

The cys-rich domain The cys-rich domain is composed of eight disulfide-bonded modules (Figure 6b), the first of which sits at the end of L1, while the remainder make a curved rod running diagonally across L1 and reaching to L2 (Figure The strands in modules 2-7 run roughly perpendicular to the axis of the rod in a manner more akin to laminin (Stetefeld, et al.,1996, J.Mol.Biol. 257:644- 657 than to TNF receptor (Banner, D. et al., 1993, Cell, 73:431-445), but the modular arrangement of the cys-rich domain is different to those of other cys-rich proteins for which structures are known. The first 3 modules of IGF- 1R have a common core, containing a pair of disulfide bonds, but show considerable variation in the loops (Figure 6b). The connectivity of these modules is the same as in the first half of EGF (Cys 1-3and but their structures do not appear to be closely related to any member of the EGF family. Modules 4 to 7 have a different motif, a 0-finger, and best match residues 2152-2168 of fibrillin (Dowling, A. et al., 1996, Cell, 85:597-605).

Each is composed of three polypeptide strands, the first and third being disulfide bonded and the latter two forming a P-ribbon. The p-ribbon of each 3- finger module lines up antiparallel to form a tightly twisted 8-stranded psheet (Figures 5 and Module 6 deviates from the common pattern,with WO 99/28347 PCT/AU98/00998 28 the first segment being replaced by an cc-helix followed by a large loop that is likely to have a role in ligand binding (see below). As module 5 is most similar to module 7 it is possible that the four modules arose from serial gene duplications. The final module is a disulfide-linked bend of five residues.

The fact that the two major types of cys-rich modules occur separately implies that these are the minimal building blocks of cys-rich domains found in many proteins. Although it can be as short as 16 residues, the motif of modules 4-7 is clearly distinct, and capable of forming a regular extended structure. Thus cys-rich domains such as these can be considered as being made of repeat units each composed of a small number of modules.

Hormone binding Attempts have been made to locate the IGF-1 (and insulin) binding site by examining natural (Taylor, S. 1992, Diabetes, 41:1473-1490) and site-directed mutants (Williams, P. et al., 1995, J. Biol. Chem. 270:3012- 3016; Mynarcik, D. C et al., 1996, J. Biol. Chem. 271:2439-2442; Mynarcik, D.

et al., 1997, J. Biol. Chem. 272:2077-2081), chimeric receptors (Andersen, A. et al., 1990, Biochemistry 29:7363-7366; Gustafson, T. Rutter, W.

1990, J. Biol. Chem. 265:18663-18667; Schiffer, et al.,1993, J. Biol.

Chem. 268:3044-3047; Schumacher, 1993, J. Biol. Chem. 268:1087-1094; Kjeldsen, et al., 1991, Proc. Natl Acad. Sci. USA, 88:4404-4408) and by crosslinking studies (Wedekind, et al., 1989, Biol. Chem Hoppe-Seyler, 370:251-258; Fabry, 1992, J. Biol. Chem. 267:8950-8956; Waugh, S. et al., 1989, Biochemistry, 28:3448-3458; Kurose, et al., 1994),.J. Biol.

Chem.269:29190-29197-34). IGF-1R/IR chimeras not only show which regions of the receptors account for ligand specificity, but also provide an efficient means of identifying some parts of the hormone binding site.

Paradoxically, regions controlling specificity are not the same for insulin and IGF-1. Replacing the first 68 residues of IGF-1R with those of IR confers insulin-binding ability on the chimeric IGF-1R (Kjeldsen, et al., 1991, Proc. Natl Acad. Sci. USA, 88:4404-4408), and replacing residues 198-300 in the cys-rich region of IR with the corresponding residues 191-290 of IGF-1R allows the chimeric receptor to bind IGF-1 (Schiffer, et al.,1993, J. Biol.

Chem. 268:3044-3047). Thus a receptor can be constructed which binds both IGF-1 and insulin with near native affinity. From the structure it is clear that if the hormone bound in the central space it could contact both these regions.

WO 99/28347 PCT/AU98/00998 29 From analysis of a series of chimeras examined by Gustafson, T. Rutter, W. J. Biol. Chem. 265:18663-18667, 1990), the specificity determinant in the cys-rich region can be limited further to residues 223-274.

This region corresponds to modules 4-6, and includes a large and somewhat mobile loop (residues 255-263, mean B[Ca atoms] 57 A2) which extends into the central space (see Figure In IR this loop is four residues bigger, and is stabilised by an additional disulfide bond (Schiffer, L. Hansen, P.H.,1996, Exp. Clin. Endocrinol. Diabetes, 104: Suppl. 2, 89). The larger loop of IR may serve to exclude IGF-1 from the hormone binding site while allowing the smaller insulin molecule to bind. It is interesting to note that mosquito IR homologue, which has a loop two residues larger than the mammalian IRs, also appears to bind insulin but not IGF-1 (Graf, et al., 1997, Insect Molec.Biol. 6:151-163). Analysis of the structure indicates that the insulin/IGF-1 specificity is controlled by residues in this loop (amino acids 253-272 in IGF-1R; amino acids 260-283 in IR) As chimeras only address residues which differ between the two receptors, a more precise analysis of the site can be obtained from single site mutants. In particular, from an alanine-replacement study, four regions of L1 important for insulin binding were identified (Williams, P. et al., 1995, J.

Biol. Chem. 270:3012-3016). The first three are at similar positions on successive turns of the -helix and the fourth lies on the conserved bulge on the large P-sheet. Thus there is a footprint for insulin binding to the L1 domain which lies on the first half of the large P-sheet facing into the central space. Residues further along the sheet which are conserved in IGF-1R could also be important. The conservative substitution of leucine for methionine at residue 119 of IR (113 of IGF-1R) causes a mild form of leprechaunism [Hone, J. et al., 1994, J. Med. Genet. 31, 715-716]. This residue is buried, and the mutation could perturb neighbouring residues to affect insulin binding.

The axis of the L2 domain is perpendicular to that of the L1 domain, and the N-terminal end of its P-helix is presented to the hormone-binding site. On this face of the L2 domain the only mutation studied so far is the naturally occurring IR mutant, S323L, which gives rise to Rabson-Mendehall syndrome and severe insulin resistance (Roach, P.,1994, Diabetes 43:1096- 1102). As this mutant only affects insulin binding and not cell-surface expression, residue 323 of IR (residue 313 of IGF-1R) is probably at or near the binding site. Structurally this residue lies in the middle of a region WO 99/28347 PCT/AU98/00998 (residues 309-318 of IGF-1R) which is conserved in both IR and IGF-1R, and the surrounding region, 332-345 (of IGF-1R), is also quite well conserved in the these receptors (Figure 6a). Therefore this region is quite likely to form part of the hormone-binding site, but would not have been detected by chimeras. It is interesting to note that in this region IRR is not as well conserved as the other two receptors (Shier, P. Watt, 1989, J.Biol.Chem. 264:4605-14608).

The distance from this putative hormone-binding region on L2 to that found on L1 is about 30 A (Figure Thus L1 and L2 appear too far apart to bind IGF-1 or insulin. However, in the crystal structure there is a deep cleft between part of the cys-rich domain (residue 262)and L2 (residue 305), and this cleft is occupied by a loop from a neighbouring molecule. Thus it seems probable that the position of the L2 domain in the receptor structure or the hormone-receptor complex adopts a different position with respect to the cys-rich domain than that found in the crystal. The movement required to bring L2 sufficiently close to L1 is small, namely a rotation of approximately 250 about residue 298.

A number of IR mutants have been identified which constitutively activate the receptor, and the majority of these are found in the a chain.

Curiously all a chain mutants involve changes to or from proline or the deletion of an amino acid, implying that they cause local structural rearrangements. The mutation R86N is similar to wild type, but R86P reduces cell-surface expression and insulin binding while constitutively activating autophosphorylation [Granskov, K. et al., 1993, Biochem. Biophys.

Res. Commun. 192, 905-911]. The proline mutation probably disturbs residues preceding 87 which lie in the interface between the L1 and cys-rich domains, but it could also affect insulin binding. In the cys-rich domain residues 233, 281, 244 and 247 of IR are not conserved in IGF-1R (Figure 6b), yet L233P [Klinkhamer, M.P. et al., 1989, EMBO J. 8, 2503-2507], deletion of N281 [Debois-Mouthon, C. et al., 1996, J. Clin. Endochronol. Metab. 81, 719- 727] or the triple mutant P243R, P244R and H247D [Rafaeloff, R. et al., 1989, J. Biol. Chem. 264, 15900-15904] cause constitutive kinase activation. Due to their locations each of these three mutants appears likely to compromise the folding of a p-finger domain and, in turn, the structural integrity of the rodlike cys-rich domain. The structural ramifications of these mutations could be significant for the whole receptor ectodomain, as disturbing the Ll/cys- WO 99/28347 PCT/AU98/00998 31 rich interface or distorting the rod-like domain could affect the relative position of L1 and the cys-rich domain in this context.

L1 has been further implicated, as deletion of K121 on the opposite side of L1 from the cys-rich domain was also found to cause autophosphorylation [Jospe, N. et al., 1994, J. Clin. Endochronol. Metab. 79, 1294-1302]. By contrast this mutation does not affect insulin binding. Thus a possible mechanism emerges for insulin binding and signal transduction.

When insulin binds between L1 and L2 it modifies the relative position of L1 and the cys-rich domain in the receptor, perhaps by hinge motion between L2 and the cys-rich domain like that suggested above, and the structural rearrangement is transmitted across the plasma membrane. In the absence of insulin the same signal can be initiated by mutations in the cys-rich region or at the L/cys-rich interface, but at the expense on insulin binding. The signal can also be initiated more directly by mutations on the opposite side of L1 which affect the interaction of L1 with other parts of the ectodomain, possibly the other half of the receptor dimer.

Ligand Studies Although there is no structural information about an IGF-1/IGF-1R complex a number of studies have probed the nature of this interaction.

Results from cross-linking experiments with IGF-1 and insulin and their cognate receptors are consistent with the hormone binding site proposed above. For example B29 of insulin can be cross-linked to the cys-rich region (residues 205-316( (Yip, C. et al., 1988, Biochim. Biophys. Res. Commun.

157:321-329) or the L1 domain (Wedekind, et al., 1989, Biol. Chem Hoppe- Seyler, 370:251-258). However, these two regions are reasonably well separated, and those studies may indicate that B29 is mobile. Other studies unfortunately do not map the site any more precisely.

Analogues and site-directed mutants of IGF-1 and IGF-2 have been more fruitful. IGF-1 and IGF-2 contain two extra regions relative to insulin, the C region between B and A and a D peptide at the C-terminus. For IGF-1, replacement of the C region by a four Gly linker reduced affinity for IGF-1R by a factor of 40 but increased affinity for IR 5-fold (Bayne, M.L.,et al., 1988, J. Biol.Chem. 264:11004-11008). Changes in affinity are consistent with the deletion in IGF-1 complementing differences in the cys-rich regions of IGF- 1R and IR noted above. Mutation of residues either side of the C region (residue 24 for IGF-1 [Cascieri, et al., 1988, Biochemistry 27:3229- WO 99/28347 PCT/AU98/00998 32 3233], residues 27,43 for IGF-2, [Sakano, et al., 1991, J. Biol. Chem.

266:20626-20635]) also has deleterious effects on the affinity of the hormone for IGF-1R, as has truncation of the nearby D peptide in IGF-2 (Roth, et al., 1991, Biochem. Biophys. Res. Commun. 181:907-914).

Insulin has been extensively mutated. Binding studies [summarised in Kristensen, C. et al., 1997, J. Biol. Chem. 272, 12978-12983] indicate that insulin may bind its receptor via a hydrophobic patch (residues A2, A3, A19, B8, B11, B12, B15 and possibly B23 B24). However this patch is normally buried, and requires the removal of the B chain's C-terminus from the observed position. Assuming IGF-1, IGF-2 and insulin bind their receptors in the same orientation, these data suggest an approximate orientation for the hormone when bound to the receptor.

One notable feature of IGF-1 and IGF-2 is the large number of charged residues and their uneven distribution over the surface. Basic residues are predominantly found in the C region and, in solution, this region is not well ordered in either IGF-1 or -2 (Sato, et al., 1993, Int J Peptide Protein Res. 41:433-440; Torres, A. et al., 1995,J. Mol. Biol. 248:385-401).

In contrast the binding site of the receptor has a sizable patch of acidic residues in the corner where the cys-rich domain departs from L1. Other acidic residues which are specific to this receptor are found along the inside face of the cys-rich domain and the loop (residues 255-263) extending from module 6. Thus it is possible that electrostatic interactions play an important part in IGF-1 binding, with the C region binding to the acidic patch of the cys-rich region near L1 and the acidic patch on the other side of the hormone directed towards a small patch of basic residues (residues 307-310) on the N-terminal end of L2.

Although the structure of this fragment gives significant information about the nature of the hormone binding site, residues outside this region have also been shown to affect binding of ligand. A number of studies have implicated residues 704-715 of IR (Mynarcik, D. C et al., 1996, J. Biol. Chem.

271, 2439-2442; Kurose, et al., 1994, J. Biol. Chem.269:29190-29197).

These residues could contact insulin on one of the sides left open in the current structure. Using insulin labelled at the B1 residue, Fabry, et al.,(1992, J. Biol. Chem. 267:8950-8956) cross-linked insulin to the fragment 390-488, part of which is not near the site as described. The explanation for this could be either the region 390-488 reaches back to the hormone binding WO 99/28347 PCT/AU98/00998 33 site, or this region could contact another hormone bound to the other half of the receptor. Further structural information is needed to establish how these other regions contact the hormone and to elucidate how binding of the hormone is communicated to the kinase inside the cell.

The structure of the L1-cys-rich-L2 domains of IGF-1R presented here represents the first structural information for the extracellular portion of a member of the insulin receptor family. The L domains display a novel fold which is common to the EGF receptor family, and the modular architecture of the cys-rich domain implies that smaller building blocks should be used to describe the composition of cysteine-rich domains. This fragment contains the major specificity determinants of receptors of this class for their ligands.

It has an elongated structure with a space in the middle which could accommodate the ligand. The three sides of this site correspond to regions which have been implicated in hormone binding. Although other sites are present in the receptor ectodomain which interact with the ligand, this structure gives us an initial view of how the insulin, IGF-1 and IGF-2 might interact with their cell surface receptors to control their metabolic and mitogenic effects Such information will provide valuable insight into the structure of the corresponding domains of the IR and insulin receptor-related receptor as well as members of the related EGFR family (Bajaj, et al., 1987, Biochim Biophys Acta 916:220-226; Ward, C. W. et al., 1995, Proteins: Struct Funct Genet 22:141-153).

EXAMPLE 3 Prediction of 3D Structure of the Corresponding Domains of IRR and IR Based on Structure of IGF-1R Fragment.

The sequence identities between the different members of the insulin receptor family are sufficient to allow accurate sequence alignments to facilitate 3D structure predictions by homology modelling. The alignments of the ectodomains of human IGF-1R, IR, and IRR are shown in Figure 9.

EXAMPLE 4 Single-Molecule Imaging of Human Insulin Receptor Ectodomain and its Fab Complexes Cloning and expression of hIR -11 ectodomain protein A full length clone of the human IR exon -11 form (hIR -11) was prepared by exchanging an Aat II fragment, nucleotides 1195 to 2987 of the WO 99/28347 PCT/AU98/00998 34 exon +11 clone (plasmid pET; Ellis et al., 1986; gift from Dr W. J. Rutter, UCSF) of hIR (Ebina et al., 1985, Cell 40, 747-758) with the equivalent Aat II fragment from a plasmid (pHIR/P12-1, ATCC 57493) encoding part of the extracellular domain and the entire cytoplasmic domain of hIR -11 (Ullrich et al., 1985, Nature 313 756-761). The ectodomain fragment of hIR -11 (2901 bp, coding for the 27 residue signal sequence and residues His1- Asn914) was produced by Sail and SspI digestion and inserted into the mammalian expression vector pEE6.HCMV-GS (Celltech Limited, Slough, Berkshire, UK) into which a stop codon linker had been inserted, as described previously (Cosgrove et al., 1995, Protein Expression and Purification 6, 789-798) for the hIR exon +11 ectodomain.

The resulting recombinant plasmid pHIR II (2 jg) was transfected into glycosylation-deficient Chinese hamster ovary (Lec 8) cells (Stanley, 1989, Molec. Cellul. Biol. 9, 377-383) with Lipofectin (Gibco-BRL). After transfection, the cells were maintained in glutamine-free medium GMEM (ICN Biomedicals, Australia) as described previously (Bebbington Hentschel, 1987, In DNA Cloning (Glover, ectodomain.), Vol III, Academic Press, san Diego; Cosgrove et al., 1995, Protein Expression and Purification 6, 789-798). Expressing cell lines were selected for growth in GMEM with M methionine sulphoximine (MSX, Sigma). Transfectants were screened for protein expression using sandwich ELISA with anti-IR monoclonal antibodies 83-7 and 83-14. Metabolic labelling of cells, immunoprecipitations, insulin binding assays and Scatchard analyses were performed as described previously for the exon +11 form of hIR ectodomain (Cosgrove et al., 1995, Protein Expression and Purification 6, 789-798).

hlR -11 ectodomain production and purification The selected clone (inoculum of 1.28 x 108 cells) was grown in a spinner flask packed with 10 g of Fibra-cel disc carriers (Sterilin, in 500 ml of GMEM medium containing 10% fetal calf serum (FCS) and 25 tM MSX.

Selection pressure was maintained for the duration of the culture.

Ectodomain was recovered from harvested medium by affinity chromatography on immobilized insulin, and further purified by gel filtration chromatography on Superdex S200 (Pharmacia; 1 x 40 cm) in Tris-buffered saline containing 0.02% sodium azide (TBSA) as described previously (Cosgrove et al., 1995, Protein Expression and Purification 6, 789-798).

Solutions of purified hIR -11 ectodomain were stored at 40 C prior to use.

WO 99/28347 PCT/AU98/00998 Production of Fab fragments and their complexes with ectodomain Purification of Mabs 83-7, 83-14 and 18-44 from ascites fluid by affinity chromatography using Protein A-Sepharose, and the production of Fabs, were based on the methodologies described in Coligan et al.,1993, Current Protocols in Immunology, Vol 1, pp 2.7.1-2.8.9, Greene Publishing Associates Wiley Interscience, John Wiley and Sons. Fab was produced from monoclonal antibody by mercuripapain digestion for 1-4 h, followed by gel filtration on Superdex S200. Products were monitored by reducing and non-reducing SDS-PAGE. For 83-7 Mab, an IgG Type 1 monoclonal antibody, the bivalent (Fab)2' isolated by this method was reduced to monovalent Fab 83-7 by mild reduction with mM L-cysteine.HCl in 100 mM Tris pH (Coligan et al., 1993, Current Protocols in Immunology, Vol 1, pp 2.7.1-2.8.9, Greene Publishing Associates Wiley Interscience, John Wiley and Sons).

Complexes of Fab with hIR -11 ectodomain were produced by mixing 2.5 to 3.5 molar excess of Fab with hIR -11 ectodomain at ambient temperature in TBSA at pH 8.0. After 1-3 h, the complex was separated from unbound Fab by gel filtration over a Superdex S200 column in the same buffer.

Electron microscopy Uncomplexed hIR -11 ectodomain and the Fab complexes described above were diluted in phosphate-buffered saline (PBS) to concentrations of the order of 0.01-0.03 mg/ml. Prior to dilution, 10% glutaraldehyde (Fluka) was added to the PBS to achieve a final concentration of 1% glutaraldehyde.

Droplets of 3ml of this solution were applied to thin carbon film on 700mesh gold grids after glow-discharging in nitrogen for 30 s. After 1 min. the excess protein solution was drawn off and followed by application and withdrawal of 4-5 droplets of negative stain uranyl acetate (Agar), 2% uranyl formate K and 2% potassium phosphotungstate (Probing and Structure) adjusted to pH 6.0 with KOH, or 2% methylamine tungstate (Agar) adjusted to pH 6.8 with NH40H]. In the case of both uranyl acetate and uranyl formate staining, an intermediate wash with 2 or 3 droplets of PBS was included prior to application of the stain. The grids were air-dried and WO 99/28347 PCT/AU98/00998 36 then examined at 60kV accelerating voltage in a JEOL 100B transmission electron microscope at a magnification of 100,000x. It was found that there was a typical thickness of negative stain in which Fabs were most easily seen. Hence areas for photography had to be chosen from particular zones of the grid. Electron micrographs were recorded on Kodak SO-163 film and developed in undiluted Kodak D19 developer. The electron-optical magnification was calibrated under identical imaging conditions by recording single-molecule images of the antigen-antibody complex of influenza virus neuraminidase heads and NC10 MFab (Tulloch et al., 1986, J.Mol. Biol. 190, 215-225; Malby et al., 1994, Structure, 2, 733-746).

Image processing Electron micrographs showing particles in a limited number of identifiable projections were chosen for digitisation. Micrographs were digitised on a Perkin-Elmer model 1010 GMS PDS flatbed scanning microdensitometer with a scanning aperture (square) size of 20 mm and stepping increment of 20 mm corresponding to a distance of 0.2 nm on the specimen. Particles were selected from the digitised micrograph using the interactive windowing facility of the SPIDER image processing system (Frank et al., 1996, J. Struct. Biol. 116, 190-199). Particles were scaled to an optical density range of 0.0 2.0 and aligned by the PSPC reference-free alignment algorithm (Marco et al., 1996, Ultramicroscopy, 66, 5-10). Averages were then calculated over a subset of correctly aligned particles chosen interactively as being representative of a single view of the particle. The final average image presented here is derived from a library of 94 images.

Biochemical characterization of expressed hIR -11 ectodomain The recombinant protein examined corresponded to the the first 914 residues of the 917 residue ectodomain of the exon -11 form of the human insulin receptor (Ullrich et al., 1986, Nature 313 756-761). Expressed protein was shown, by SDS-PAGE and autoradiography of immunoprecipitated product from metabolically labelled cells, to exist as a homodimeric complex of -270 320 kDa apparent mass, which dissociated under reducing conditions into monomeric ac and p' subunits of respective apparent mass -120 kDa and -35 kDa (data not shown).

Purified hIR -11 ectodomain, expressed in Lec8 cells and purified by affinity chromatography on an insulin affinity column, eluted as a symmetrical peak on a Superdex S200 gel filtration column (Figure 10). The WO 99/28347 PCT/AU98/00998 37 protein eluted with an apparent mass of -400 kDa, calculated from a standard curve generated by the elution positions of standard proteins (not shown). As expected for protein expressed in Lec 8 cells, whose glycosylation defect produces truncated oligosaccharides (Stanley, 1989,.

Molec. Cellul. Biol. 9, 377-383), this value is less than the apparent mass (450 500 kDa) reported for hIR +11 ectodomain expressed in wild-type CHO-K1 cells (Johnson et al., 1988, Proc. Nat Acad. Sci USA 85, 7516-7520; Cosgrove et al., 1995, Protein Expression and Purification 6, 789-798).

Radioassay of insulin binding to purified ectodomain gave linear Scatchard plots and Kd values of 1.5 1.8 x 10-9 M, similar to the values of 2.4 5.0 x 10-9 Ml reported for the hIR -11 ectodomain (Andersen et al., 1990, Biochemistry 29, 7363-7366; Markussen et al., 1991, J. Biol. Chem. 266, 18814-18818; Schaffer, 1994, Eur. J. Biochem. 221, 1127-1132) and the values of -1.0 5.0 x 10-9 M reported for the hIR +11 ectodomain (Schaefer et al., 1992, 1. Biol. Chem. 267, 23393-23402; Whittaker et al., 1994, Molec.

Endocrinol. 8, 1521-1527; Cosgrove et al., 1995, Protein Expression and Purification 6, 789-798).

Expression of hIGF-1R ectodomain Cloning, expression and purification of this protein used elements common to those described for hIR -11 ectodomain (Cosgrove et al., 1995, Protein Expression and Purification 6, 789-798), and resulted in purified product that was recognised by receptor-specific Mabs 17-69, 24-31 and 24-60 (Soos et al., 1992, J. Biol. Chem. 267, 12955-63) and was composed of a and P' subunits of mass similar to those of hIR ectodomain.

Preparation of hIR -11 ectodomain/MFab complexes A complex of hIR -11 ectodomain and Fab from antibody 83-14 eluted as a symmetrical peak of 460 -500 kDa (Figure 10), as did complexes generated from a mixture of hIR -11 ectodomain with Fab from antibody 18- 44 and a mixture of hIR -11 ectodomain with Fab 83-7 (not shown). A cocomplex of ectodomain with Fabs from antibodies 18-44 and 83-14 eluted at 620 kDa, as did a co-complex with MFabs 83-14/83-7 and another with MFabs 83-7/18-44 (not shown). A complex of hIR -11 ectodomain with all three MFab derivatives, 18-44, 83-7 and 83-14, eluted at an apparent mass of 710 kDa (Figure Electron microscopy Imaging of hIR -11 and hIGF-1R ectodomains WO 99/28347 PCT/AU98/00998 38 Single-molecule imaging of uncomplexed dimeric hIR -11 ectodomain was carried out under a variety of negative staining conditions, which emphasised different aspects of the structure of the molecular envelope. Images obtained by this investigation are depicted in Figure 11.

The least aggressive or penetrative stain was potassium phosphotungstate (KPT) which revealed consistent globular particles with very little internal structure other than a suggestion of a division into two parallel bars. Staining with methylamine tungstate also revealed the parallel bar images.

Further investigation using progressively more penetrative, but also potentially more disruptive, stains confirmed the observations above.

Staining with uranyl acetate and uranyl formate showed the separation of the parallel bars most clearly, but uranyl acetate showed evidence of disrupting the structure of the particles, i.e. a decrease in the consistency of the particle shape and a tendency for particles to look unravelled or denatured despite having been subjected to chemical cross-linking prior to staining. In areas of thicker stain, parallel bars predominated, whereas in more thinly stained regions, U-shaped particles could be identified, sometimes outnumbering the parallel-bar structures (see Figure 11).

Imaging of hIR -11 ectodomain complexed with 83-7 MFab This complex was particularly noteworthy for the consistency of the form of the particles, especially under the gentler staining conditions afforded by stains such as KPT and methylamine tungstate. The particles were interpreted as having been restricted in the views they presented, after air-drying on the carbon support film, by the almost diametrically opposite binding of the two Fab arms to the antigen to form a highly elongated complex structure. Under these conditions three distinct views could be recognised (see Figure 11). Two views (interpreted as top-down/bottom-up) show the Fab arms displaced clockwise or anti-clockwise as extensions of the parallel plates with two-fold symmetry. The third view shows an image with the two Fab arms in line roughly through the centre of the receptor on its opposite sides, interpreted as a side projection of binding half-way up the plates.

The use of aggressive uranyl stains operating at lower pHs revealed internal structure of the molecular envelope at the expense of consistency of the particle morphology. For example, staining with uranyl acetate or uranyl WO 99/28347 PCT/AU98/00998 39 formate showed that parallel bars can be seen in particles in which the Fab arms are displaced either clockwise or anticlockwise but not where the intermediate central or axial position of the two Fab arms is presented in projection. These observations show 83-7 MFab binding roughly half-way up the side-edge of each hIR -11 ectodomain plate. The epitope recognised by Mab 83-7 has been mapped to the cys-rich region, residues 191-297, by analysis of chimeric receptors (Zhang and Roth, 1991, Proc. Natl. Acad. Sci.

USA 88, 9858-9862).

Imaging of hIR -11 ectodomain complexed with either 83-14 MFab or 18-44 MFab Complexes were formed with Fabs from the most insulin-mimetic antibody Mab 83-14. Projections showing the Fab arms bound to and extending out from near the base of the U-shaped particles were identified.

A second field of particles showed objects composed of two parallel bars as observed for the undecorated ectodomain, with Fab arms projecting obliquely from diametrically opposite extremities (see Figure 11). Similar but less definitive images were also seen when MFab 18-44 was bound to hIR -11 ectodomain. The epitope for Mab 83-14 is between residues 469-592 (Prigent et al., 1990) in the connecting domain. This domain contains one of the disulphide bonds (Cys524-Cys524) between the two monomers in the IR dimer (Schaffer and Ljungqvist, 1992, Biochem. Biophys. Res. Commun. 189, 650-653). The epitope for Mab 18-44 is a linear epitope, residues 765-770 (Prigent et al., 1990, J. Biol. Chem. 265, 9970-9977) in the p-chain, near the end of the insert domain (O'Bryan et al., 1991, Mol. Cell. Biol. 11, 5016- 5031). The insert domain contains the second disulphide bond connecting the two monomers in the IR dimer (Sparrow et al., 1997, J. Biol. Chem., 272, 29460-29467).

Imaging of hIR -11 ectodomain co-complexed with two different MFabs per monomer The double complex of hIR -11 ectodomain with MFabs 83-7 and 18- 44 was stained with 2% KPT at pH 6.0, and revealed the molecular envelopes. The particle appears complex in shape, and can assume a number of different orientations on the carbon support film, giving rise to a number of different projections in the micrograph. The predominant view is of an asymmetric X-shape (some examples circled). It shows the 83-7 MFab arms bound at opposite ends of the parallel bars with the two 18-44 MFabs WO 99/28347 PCT/AU98/00998 appearing as shorter projections extending out from either side of each ectodomain.

Images of the double complex of hIR -11 ectodomain with 83-7 and 83-14 MFabs gave X-shaped images similar to those seen with the 83-7/18-44 double complex. In contrast the double complex of hIR -11 ectodomain with 18-44 and 83-14 MFabs did not present the characteristic asymmetric Xshapes described above. Instead, the molecular envelope appeared to be elongated in many views, with only an occasional X-shaped projection.

While a detailed interpretation of these images would be premature, it is clear that MFabs 18-44 and 83-14, two of the more potent insulin mimetic antibodies (Prigent et al., 1990, J. Biol. Chem. 265, 9970-9977), can bind simultaneously to the receptor.

Imaging of hIR -11 ectodomain co-complexed with three different MFabs per monomer A field of particles from a micrograph of hIR -11 ectodomain were complexed simultaneously with MFabs 83-7, 83-14 and 18-44. In the thicker stain regions the molecular envelope was X-shaped, and looked very similar to that of the double complexes of hIR -11 ectodomain with either 83-7 and 18-44 or 83-7 and 83-14. However, in the more thinly stained regions particles of greater complexity were visible, and it was possible occasionally to identify that there are in fact more than four IMFabs bound to the ectodomain dimer.

The single-molecule imaging of hIR -11 ectodomain presented here suggests a molecular envelope for this dimeric species significantly different from that of any previously published study. However, an unequivocal determination of the molecular envelope even from the present study is not entirely straightforward. A major complicating factor here has been the relative fragility of the expressed ectodomain when exposed to the rigors of electron microscope preparation by negative staining. For example, staining with potassium phosphotungstate KPT, pH 6.0-7.0) frequently suggested a denaturation of the dimeric molecules, but when appropriate conditions were satisfied, good seemingly interpretable molecular envelope images were achieved; staining with methylamine tungstate pH supported the best KPT molecular envelope images, but had the suggestion of a swelling of the molecular structure at neutral pH; and the acid-pH stains of uranyl acetate pH and uranyl formate pH-3.0), with their ability to penetrate the WO 99/28347 PCT/AU98/00998 41 ectodomain structure, appeared to illuminate not so much the molecular envelope as the zones of high projected protein density within the dimer.

An amalgam of impressions from these various staining regimens has led to the following interpretation of single-molecule images of these undecorated, or naked, dimers: the predominant dimeric molecular image encountered here has been that of "parallel bars"of projected protein density.

This view is so predominant, indeed, that it suggests there is either a single preferred orientation of the molecules on the glow-discharged carbon support film, or that this impression of parallel bars of density may represent a mixture of superficially similar structure projections, with the subtleties of these different projections being masked by the relatively coarse resolution of this single-molecule direct imaging. The impression of parallel bars of projected protein density is particularly predominant in regions of thicker negative stain. A second view of the molecular envelope, appreciably less well represented in regions of thicker stain but predominant in regions of thin staining, is that of 'open' U's, or V's. These two views of hIR -11 ectodomain were supported by the single-molecule imaging of hIGF-1R ectodomain under comparable conditions of negative staining.

If the assumption is made that these two recognisable projected views, that of parallel bars and of open U's/V's, are different views of the same dimeric molecule, an assumption strongly supported by the MFab complex imaging, a coarse model of the molecular envelope can be rationalized. The model structure is roughly that of a cube, composed of two almost-parallel plates of high protein density, separated by a deep cleft of low protein main-chain and side-chain density able to be penetrated by stain, and connected by intermediate stain-excluding density near what is assumed here to be their base that is, nearest the membrane-anchoring region). The width of the low-density cleft appears to be of the order of 30-35A, sufficient to accommodate the binding of the insulin molecule of diameter ca. although we have no electron microscopical evidence to support insulinbinding in this cleft at this stage.

It has been established through imaging of bound 83-7 MFab that there is a dimeric two-fold axis normal to the membrane surface between these plates of density. Occasionally, dimer images display a relative displacement of the bars of density, interpreted here as a limited capacity for a shearing of the interconnecting zone between the two plates along their WO 99/28347 PCT/AU98/00998 42 horizontal axis parallel to the membrane; other images show bars skewed from parallel, implying a limited capacity for the plates to rotate independently around the two-fold axis, again via this interconnecting zone.

These two observations each suggest a relatively flexible connectivity between the dimer plates in the membrane-proximal region of intermediate protein density, which could possibly contribute to the transmembrane signalling process.

The approximate overall measured dimensions of the ectodomain dimer are 110 x 90 x 120A, calibrated against the dimensions of imaged influenza neuraminidase heads, known from the solved X-ray structure (Varghese et al., 1983, Nature 303, 35-40). It can be noted that there is a compatibility here between the molecular weights and molecular dimensions of these two molecular species: the compact tetrameric influenza neuraminidase heads of Mr -200 kDa occupy a volume almost 100 x 100 x 60 A; the more open dimeric insulin receptor ectodomains of similar Mr -240 kDa imaged here occupy a volume approximately 110 x 90 x 120 A roughly twice that of the neuraminidase heads, accommodating the slightly higher molecular weight and substantial central low-density cleft.

The low-resolution roughly cubic compact structure proposed here differs substantially from the T-shaped model proposed by Christiansen et al.

(1991, Proc. Natl. Acad. Sci. U. S. A. 88, 249-252) and Tranum-Jensen et al., (1994, J. Membrane Biol. 140, 215-223) for the whole receptor and the elongated model proposed by Schaefer et al. (1992,J. Biol. Chem. 267, 23393- 23402) for soluble ectodomain. Significantly, those previous studies did not provide any convincing independent electron microscopical evidence that their imaged objects were in fact insulin receptor.

In the present study, the identity of the imaged molecules as hIR -11 ectodomain has been confirmed by imaging complexes of the dimer with Fabs of the three well-established conformational Mabs against native hIR, 83-7, 83-14 and 18-44 (Soos et al.,1986, Biochem. J. 235, 199-208; 1989, Proc.

NatlAcad. Sci. USA 86, 5217-5221), bound singly and in combination. In all these instances, virtually every particle in the field of view exhibited MFab decoration through binding to conformational epitopes, establishing not only the identity of the imaged particles but also the conformational integrity of the expressed ectodomains. Furthermore, the cleanliness and uniformity of these hIR -11 ectodomain preparations, both naked and decorated, visualised WO 99/28347 PCT/AU98/00998 43 here by electron microscopy demonstrate their high suitability for X-ray crystallization trials.

The known flexibility of the Fab arms exacerbates image-to-image variability beyond the limited extent already described for the undecorated dimeric ectodomains, complicating any precise interpretation of these antigen-antibody complexes. Such molecular flexibility also renders largely impractical any single-molecule computer image averaging to facilitate image interpretation, progressively more so with the higher order antigen-antibody complexes studied here.

The most readily interpretable of these images, showing least imageto-image variability, are those of 83-7 MFab bound to dimers where, fortuitously, the antigen-antibody complex is constrained in its degrees of rotational freedom on the carbon support film. Many projected images show the two Fab arms in line roughly through the centre of the antigen on its opposite sides, interpreted as a side projection of binding half-way up the plates from their membrane-proximal base. Other sub-sets of images show the two Fab arms still parallel but displaced clockwise or anticlockwise with 2-fold symmetry, each Fab approximating an extension of one of the parallel bars of antigen density, interpreted here as representing top or bottom projections along the 2-fold axis. The third projection, along the axis of the Fab arms, could not be sampled here because of the constraining geometry of this molecular complex. These observations suggest binding of 83-7 MFab roughly half-way up the side-edge of the hIR -11 ectodomain plate. This then allows an initial attempt at spatially mapping the 83-7 MFab epitope, which has been sequence-mapped to residues 191-297 in the cys-rich region of the insulin receptor (Zhang and Roth, 1991, Proc. Natl. Acad. Sci. USA 88, 9858- 9862). The spatial separation and relative orientations of the two binding epitopes of Mab 83-7 on the hIR -11 ectodomain dimer as indicated here appear inconsistent with the proposal that Mab 83-7 could bind intramolecularly to hIR (O'Brien et al., 1987, Biochem J. 6, 4003-4010).

Decoration of the ectodomain dimer with 83-7 MFab established that the two plates of high protein-density are arranged with 2-fold symmetry.

Decoration with either 83-14 or 18-44 MFab on the other hand, allowed sampling of the third projection of the ectodomain dimer precluded by 83-7 MFab binding. Significantly, this third view established unequivocally the Ushaped projection of the hIR -11 ectodomain dimer, something which was WO 99/28347 PCT/AU98/00998 44 only able to be assumed with the undecorated ectodomain images. Further, this projection has allowed a rough spatial mapping close to the base of the U-shaped dimer for the epitopes recognised by 83-14 MFab (residues 469-592, connecting domain) and 18-44 MFab (residues 765-770, b-chain insert domain; exon 11 plus numbering, Prigent et al., 1990, J. Biol. Chem. 265, 9970-9977).

Inherent in the model structure is the implication that, with the twofold axis aligned normal to the membrane surface, the mouth of the lowdensity cleft where insulin binding may occur would lie most distant from the transmembrane anchor, whilst the zone of intermediate density connecting the two high-density plates would be in close proximity to the membrane. It follows, in this model, that the L1/cys-rich/L2 domains(Bajaj et al., 1997, Biochim. Biophys. Acta 916, 220-226; Ward et al.,1995, Proteins: Struct., Funct., Genet. 22, 141-153), which comprise much of the insulinbinding region (see Mynarcik et al., 1997, J. Biol. Chem. 272, 2077-2081), most probably lie in the membrane-distal upper halves of the two plates, whilst the membrane-proximal lower halves contain the connecting domains, the fibronectin-type domains, the insert domains and the interchain disulphide bonds (Schaffer and Ljungqvist, 1992, Biochem. Biophys. Res.

Commun. 189, 650-653; Sparrow et al., 1997,J. Biol. Chem., 272, 29460- 29467). Such a disposition of domains is supported by the images seen with the single MFab decoration, the 83-7 vMFab epitope in the cys-rich region being spatially mapped roughly half-way up the side-edge of the ectodomain plates, and the 83-14 and 18-44 MFab epitopes (connecting domain and 0chain insert domain, respectively) being mapped near the base of the plates.

Our preference is for a single a-be monomer to occupy a single plate, although the possibility of a single monomer straddling the two plates of protein density cannot be discounted.

The more complex images involving co-binding of two, and even more so of all three, MFabs to each monomer of the ectodomain dimer are not easily interpretable with respect to relative domain arrangements within the monomer at present, not least of all because of the difficulty of finding conditions of negative staining that will simultaneously maintain the integrity of the Fab binding while highlighting recognisable and reproducible details of the internal structure of the dimeric IR ectodomain.

WO 99/28347 PCT/AU98/00998 The data presented here demonstrate the ability of single-molecule imaging to give an initial insight into the topology of multidomain structures such as the ectodomain of hIR, and the value of combining this technique with that of either single or multiple monoclonal Fab attachment per monomer as a potential means of epitope, and domain, mapping of the structure. By imaging Fab complexes of other members of the family, such as hIGF-1R ectodomain, and combining available sequence-mapped epitope information with that presented here, a more comprehensive understanding of domain arrangements within the IR family ectodomains should be forthcoming.

EXAMPLE Structure-Based Design of Ligands for the IGF Receptor as Potential Inhibitors of IGF Binding The structure of IGF receptor can be considered as a filter or screen to design, or evaluate, potential ligands for the receptor. Those skilled in the art can use a number of well known methods for de novo ligand design, such as GRID, GREEN, HSITE, MCSS, HINT, BUCKETS, CLIX, LUDI, CAVEAT, SPLICE, HOOK, NEWLEAD, PRO LIGAND, ELANA, LEGEND, GenStar, GrowMol, GROW, GEMINI, GroupBuild, SPROUT, and LEAPFROG, to generate potential agonists or antagonists for IGF-1R. In addition, the IGF-1R structure may be used as a query for database searches for potential ligands.

The databases searched may be existing eg ACD, Cambridge Crystallographic, NCI, or virtual. Virtual databases, which contain very large numbers (currently up to 1012) of chemically reasonable structures, may be generated by those skilled in the art using techniques such as DBMaker, ChemSpace, TRIAD and ILIAD.

The IGFR structure contains a number of sites into which putative ligands may bind. Search strategies known to those skilled in the art may be used to identify putative ligands for these sites. Examples of two suitable search strategies are described below: Database Search The properties of key parts of the putative site may be used as a database search query. For example, the Unity 2.x database software may be used. A flexible 3D search can be run in which a "directed tweak" algorithm is used to find low energy conformations of potential ligands which satisfy the query.

(ii) Do novo design of ligands WO 99/28347 PCT/AU98/00998 46 The Leapfrog algorithm as incorporated in the software package, Sybyl version 6.4.2 (Tripos Associates, St Louis), may be used to design potential ligands for IGF-1R sites. The coordinates of residues around the site may be taken from the x-ray structure, hydrogens and charges (Kollman all atom dictionary charges) added. From the size, shape and properties of the site, a number of potential ligands may be proposed. Leapfrog may be used to optimize the conformation of ligands and position on the site, to rank the likely strength of binding interactions with IGF-1R, and to suggest modifications to the structures which would have enhanced binding.

It is also possible to design ligands capable of interacting with more than one site. One way in which this may be done is by attaching flexible linkers to ligands designed for specific sites so as to join them. The linkers may be attached in such a way that they do not disrupt the binding to individual sites.

All references cited above are incorporated herein in their entirety by reference.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

EDITORIAL NOTE NO. 15521/99 The sequence listing is numbered from page 1-58.

The claims pages follow, starting from page number 47.

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WO 99/28347 PCT/AU98/00998 4/58 ATOll .312 C'B IEU 32 41.127 9.515 .1 6' 3 .00 47.4.? AAAA C ATOll 313 CG3 LEU 3 2 12.091 10.688 47.562 1.00 45.33 AAAA C ATOll 31-I CD] LE' 32 .11.517 11.812 .16.673 1 .00 35. 77 AAA C ATOll 315 CD2 LEU- 32 42.371 11.229 .18.96U 1.00 49.18 AAAA C ATOll 316 C LEU 32 .12.136 7.296 17.353 1.00 51.00 AAAA C ATOH 317 0 LEU 32 ,13.338 7.370 .7.186 1.00 41.36 AAAA 0 ATOM 318 II LEU 33 41.270 6.722 .16.497 1.00 50.74- AAAA II ATOM 320 CA LEU 33 11.602 6.175 45.197 1.00 49.92 AAAA C ATOll 321 CB LEU 33 42.091 7.262 .14.182 1.00 34.83 AAAA C ATOM 322 CG LEU 33 41.233 8.537 .14.164 1.00 33.92 AAAA C ATOl 323 CDI LEU 33 41.892 9.587 43.298 1.00 37.49 AAAA C ATOll 324 CD2 LEU 33 39.823 8.313 43.644 1.00 33.01 AAAA C ATOll 325 C LEU 33 42.618 5.073 .15.287 1.00 48.35 AAAA C ATOM 326 0 LEU 33 43.580 5.077 44.538 1.00 54.14 AAAA 0 ATOM 327 II ILE 34 42.543 4.212 46.254 1.00 47.61 AAAA H ATOM 329 CA ILE 34 43.523 3.184 .16.540 1.00 51.70 AAAA C ATOI 330 CB ILE 34 44.101 3.346 47.963 1.00 57.98 AAAA C ATOll 331 CG2 ILE 34 44.538 2.043 48.600 1.00 48.98 AAAA C ATOM 332 CG1I LE 34 45.267 4.371 417.967 1.00 46.70 AAAA C ATOM 333 CDI ILE 34 15.561 .1.70.1 .19.439 1.00 66.47 AAAA C ATOM 334 C ILE 34 42.829 1.844 46.408 1.00 59.85 AAAA C ATOM 335 0 ILE 34 41.726 1.531 46.856 1.00 60.11 AAAA 0 ATON 336 II1 SER 35 43.622 0.833 .16.013 1.00 67.79 AAAA H1 ATOll 338 CA SER 35 43.048 -0.511 45.922 1.00 68.80 AAAA C ATOM 339 CL SER 35 42.767 -0.882 ,14.469 1.00 64.16 AAAA C ATOM 340 OG SER 35 41.731 -1.846 4-1.1.498 1.00 75.76 AAAA 0 ATOll 342 C SER 35 43.928 -1.56.1 46.537 1.00 70.73 AAAA C ATOMl 343 0 SER 35 44.885 -1.954 45.909 1.00 73.65 AAAA 0 ATOM 344 II LYS 36 43.687 -2.017 47.740 1.00 74.75 AAAA II ATOll 346 CA LYS 36 44.465 -3.014 .18.421 1.00 76.09 AAAA C ATOll 317 CB LYS 36 44.046 -3.131 49.885 1.00 81.22 AAAA C ATOll 3.18 CG LYS 36 45.147 -3.654 50.775 1.00 78.87 AAA C ATOll 349 CD LYS 36 44.693 -4.575 51.887 1.00 81.39 AAAA C ATOM 350 CE LYS 36 44.890 -6.025 51.492 1.00 89.38 AAAA C ATOll 351 11 LYS 36 44.371 -6.989 52.506 1.00 91.63 AAAA II ATO 355 C LYS 36 44.252 -4.362 47.753 1.00 81.41 AAAA C ATOM 356 0 LYS 36 43.145 -4.772 47.451 1.00 78.20 AAAA O ATOll 357 11 ALA 37 45.371 -5.080 47.615 1.00 88.27 AAAA 11 ATOM 359 CA ALA 37 45.361 -6.396 46.986 1.00 90.10 AAAA C ATOll 360 CB ALA 37 46.700 -6.655 46.327 1.00 95.49 AAAA C ATOM 361 C ALA 37 45.011 -7.473 47.995 1.00 92.36 AAAA C ATOll 362 0 ALA 37 45.668 -7.627 .19.012 1.00 92.35 AAAA 0 ATOM 363 II SER 38 44.031 -8.301 47.622 1.00 94.31 AAAA II ATOM 365 CA SER 38 43.528 -9.352 48.484 1.00 95.70 AAAA C ATOM 366 CB SER 38 42.405 -10.164 .17.858 1.00 97.44 AAAA C ATOM 367 OG SER 38 42.061 -11.176 48.814 1.00103.48 AAAA 0 ATOM 369 C SER 38 44.702 -10.263 .18.821 1.00 96.87 AAAA C ATOM 370 0 SER 38 44.761 -10.778 49.924 1.00 98.06 AAAA O ATOMl 371 II ASP 39 45.584 -10.415 47.852 1.00 97.99 AAA II ATOH 373 CA ASP 39 46.821 -11.148 47.980 1.00 99.19 AAAA C ATOM 374 CB ASP 39 47.579 -11.050 46.652 1.00102.13 AAAA C ATOM 375 CG ASP 39 47.696 -12.387 45.949 0.01101.22 AAAA C ATOll 376 OD1 ASP 39 46.644 -12.978 45.623 0.01101.42 AAAA 0 ATOM 377 OD2 ASP 39 48.833 -12.848 .15.718 0.01101.41 AAAA 0 ATOM 3178 C ASP 39 47.660 -10.564 49.105 1.00 99.40 AAAA C ATOll 379 0 ASP 39 47.692 -11.056 50.224- 1.00 99.15 AAAA 0 ATOM 380 II TYR 40 48.354 -9.479 48.818 1.00100.96 AAAA II ATOI. 382 CA TYR 40 49.120 -8.706 49.802 1.00101.16 AAAA C ATOM 383 CB TYR 40 49.511 -7.393 19.130 1.00103.67 AAAA C ATOI 384 CG TYR 40 50.159 -6.281 49.887 1.00107.81 AAAA. C ATOll 385 CD1 TYR 40 50.931 -5.325 49.228 1.00109.56 AAAA C ATOll 386 CE1 TYR 40 51.540 -4.280 49.910 1.00109.67 AAAA C ATOll 387 CD2 TYR 40 50.04.1 -6.115 51.25.1 1.00109.28 AAAA C ATOM 388 CE2 TYR 40 50.618 -5.102 51.976 1.00109.83 AAAA C ATOll 389 C2 TYR IJ 51.372 1.181 51.276 1.00110.16 ;,AAAA C ATOll 390 OH TYF, 40 51.999 -3.127 51.893 1.00109.81 AAAA 0 ATOll 392 C TYR 40 48.343 -8.529 51.100 1.00 99.10 jAAAA C ATOll 393 0 TYR -10 .17.168 -8.182 51.183 1.00 99.05 A.AAA 0 ATOMl 394 II LYS 4] 49.041 -8.653 52.218 1.00 98.62 AAAA II ATOH 396 CA LYS 41 48.443 -8.549 53.546 1.00100.30 AAAA C ATOI 397 CB LYS 41 49.385 -9.160 54.599 1.00104.42 AAAA C ATOll 398 CG LYS 41 49.218 -10.649 54.81.1 0.01101.06 AAAA C ATOll 399 CD LYS 41 47.776 -11.107 54.919 0.01100.66 AAAA C ATOM 400 CE LYS 41 47.205 -10.880 56.308 0.01 99.86 AAAA C ATOM 401 llZ LYS .11 47.882 -11.728 57.328 0.01 99.62 AAAA II ATOll 405 C 1.YS 41 48.035 -7.136 53.917 1.00 98.99 AAAA C ATOll 406 0 LYS .11 47.615 -6.371 53.057 1.00103.33 AAAA 0 ATOM 407 !I SER 42 48.198 -6.754 55.221 1.00 91.75 AAAA lii ATO .09 CA SER 42 47.825 -5.412 55.604 1.00 85.06 AAAA C ATOll 410 CB SER 42 46.385 -5.520 56.147 1.00 95.33 AAAA C ATOM 1 411 OG SEP. 42 46.547 -6.1.10 57.426 1.00104.63 ,.AA 0 ATOll 413 C SER 42 18.628 -4.715 56.687 1.00 80.78 A.AA ATOll 414 0 SEF, 42 49.326 -5.259 57.538 1.00 81.03 -AAA 0 ATOM .15 II TYR 43 48.495 -3.395 56.673 1.00 73.03 AAAA I: ATOll 417 CA TYR 43 49.069 -2.488 57.635 1.00 67.25 AAAA C WO 99/28347 PCT/AU98/00998 ATO!l I ATO: I ATO1 I ATO! 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2 LEOJ C LEO 0 LEO' I I TY R C A TYR CB TYR CG TYP.R CDl TYR CEl TYR CD2 TYR CE2 TYRK CZ TYR O1l TY R C TYR 0 TYR I I AS11 CA ASH CGI ASO CC AS11 C A Sih 1: LIEO CA LEO C8 LEO CG LEO CDl LEO CDC2 LEOL C LE O CA A- 34 .885I 36. 11 r 3 1. 237 34.7.17 36.2 'I1 36. 494 36 .847 36.308 34 .522 34 .752 34 .308 34. 3241 34.185 34 .323 35.785 33.817 33. 163 32 .0418 33. 451 32. 3C4 32.801 32.7)60 32. 9841 33.772 34.098- 31. 970 30. 978 32. 68 5 32 2 99 32. 294 33. 6G2 341 5 79 33. 931 33.209 34 .160 32.822 33.675 32. 983 34 097 31.835 31.6C29 34 854 35. 9-70 34 .61l8 35.477 36.279 37 .023 36.1930 36. 763 36. 4 96 36. 94 3 36.'7 1 0 38.4112 36.312 35E,. 9 50 36. 704 36.329 36. 491 37. 919 38. 57 1 39.901 38. 615 39. 927 40.548 41 834 36. 989 36.6C30 37. 752 38.9093 39. 603 40C,.112_ 39.735 40.864 37. 673 38. C,4 7 3C.845 36. 473 35. 948 35.525 3 6 .60Q6 35. 199 35.484 34 449 35. 81C, 34 920 137 .1 -I 983 -4 .06c9 -1.315 -41. 849 081 6. 153 -3.838 -4 8141 -2.609 -2 .277 786 -0.296 -0.537 1 .177 986 936 863 -1 .648 -C6.075 -6 976 -8 .446 -9.160o 10. 556 -4 .055 -4 .502 071 -384 -3.292 -3 .5162 825 -4 .782 -1I. 22 4 1.0C7 4 366 0.820 2.006 3.133 2.4188 3.958 0.322 0. 669 -0.393 0. 97 2 -0.084 572 1 .2 21I 2.215 3.636 3.980 5-479 3.599 1.97(6 2.863 0.851 0.395 -1.104 -1 .559 -1.380 -1 .74 3 -2.112 505 -2.321 -2 .662 1.059 0.813 2.091 2. 979 2. 9]11 1 804 1.8C4 0. 84 S .1 .385 5. 361 .1.640 6. 04 0 6.140 482 9.513 '?.169 (.508 .874 7 .456 7 .941 10/58 419. 186 -19. 3C-1 4 9. .193 50.285 50. 001 4 8. 599 47/.688 48.408 51.163 520.13 53. 621 S3.8351 5269 5 4 .27 5 53.772 5S.213 55. 995 5-..788 5S. 127 54 .027 54.489 57.122 5-7 C 691 57.45 861 C0. 059 61.012 60. 714 5.201 58. 437 6 0.12 9 60. 340 61.0(76 61 .207 60. 092 59. 9-18 61.114 6O.84zl1 62. 192 C3.121 64 .0241 64.899 63. 913 64.771 64 .294 62. 835 62. 610 C.6(44 CC. 97 9 66. 77 9 68.071 69. 2C64 60.369 C6G.587 69.749 C-7. 322 (_.479 C8.688 CO. 997 69. 214 70. 375 69.068s 70. 223 7j. 3C3 71 268 72. 4 5.1 r69. 917 .(759- 68. 8-2 68.621 67 .213 612 65146.

60. 837 E63 S.605 1 .00 1 .00 1 .00 1 .00 1 .00 1 .00 1 .00 1 00 1 .00 1 .00 1 .00 1 .00 1 .00 1 .00 1 .00 1.00 1 00 1 .00 1 .00 1 .00 1 .00 1 .00 1 .00 1 .00 1.00 1 .00 1 .00 1 .00 1 .00 1 .00 1 00 1.00 1.00 1.00 1 .00 1 .00 1 .00 1.00 1.00 1 .00 1.00 1.00 1 .00 1.00 1.00 1 00 1 .00 1 00 1 .00 1 00 1 .00 1 .0 1 .00 1.00 1 .00 1 .00 1 .00 1.00 1. 00 1.00 1 00 1.00 1.00 1 00 1.06 1 .00 1.00 01 1.0.) I -DO 1-D: 1 21 51.83 57.91 4 9. 85 45. 64 59.01 '75. 4'1 77 49 79.63 42. 58 416. 36G 37. 28 39. 9C 34.05 35.81 35.48 25. 46 43.75, 44 04 46.50 42 .76 4 1.41 49.78 58.09 73. 43 79. 13 45.29 46.23 45.131 56.95 59.88 56.01 41. .25 417.03 40.41 37.83 38.99 3B. 95 34 84 39.29 35.11 43.05 34.22 33.74 35.90 38.21 33.35 31.65 32. 13 21l.31 37.69E 31.94 31. 95 31 .87 33.33 41 .03 4 6. 665 5 1 .20C 49.44 415. 1'5 47 .08 49. 43 55.82 33. 4C 4 3.01-.

38.12 30.718 48.63 54 .01 47.22 4 43. 08 33. 82 39.8I 135.28 136.S7 I34.7-, 30.32 2 23.2'- 3 7.1I 137.31-- 34.24 033 31 0 29.F.1 PCT/AU98/00998 AAAA AAAA 0 WAA i AAAA C AAAA C AAAA C AAAA 0 AAAA C1 AAAA 0 AWA1l A.AAA C AAAA C AAA C AAAA C AAAA C AAAA C AAAA 0 AWA C AAAA C AAA C AAAA C AAAA C AAA C AAA 0 AAA C AAAA C AAAA C AAAA 0 AAA 0 WAA C WAA C WAA C WAA C WAA C W C W,,A C W 0 W C WAA C WPA C W C WAA C WAA C WAA C WAA C WAA C AAAA C WAA C WAA C WAA C AAAA 01 WAA C W 0 W C WAA C W C W C AAAA 0 W C

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ATOI I ATOI I ATOI I ATOI I ATOl- 1022 1023 10241 1025 1027 1028 1031 1034 1035 1036 1038 1044 1045 1039 1040 1041 1042 10-16 1048 1049 1050 1051 1052 1053 1054 1055 1057 1058 1059 1061 1062 1063 1064 1066 1067 1068 1069 1070 1072 1073 1076 1079 1080 1081 1083 1084 1085 1086 1088 1089 1090 1--91 1092 1094 1095 1096 1097 1098 1099 1100 1101 1103 1104 1105 1106 1107 1109 1110 1113 1116 1117 ill'/ 1118 1120 1121 1122 1123 112-1 1125 1126 1127 1129 1130 1131 1132 1133 35.568 36.3560 35.425 34.582 341.900 36.047 33.990 34.466 33.553 34.992 34.549 34.907 36.086 35.203 34.786 35.125 33.828 33.969 34.129 33.239 33.132 33.928 33.055 33.803 32.628 34.719 34.532 35.902 36.819 35. 954 33.728 33.392 33.669 33.046 33.965 33.105 33. 917 33. 511 34.045 35.162 33.454 32.701 33.379 31.567 31.082 30.470 30.471 29.920 29.086 27.708 29.745 30. 921 29.030 29.569 29.669 30.091 28.345 28.437 28.738 27.533 29.432 26.773 29.186 28.548 28.659 27.950 27.778 28.334 27.012 29.200 30.343 28.326 28.612 28.457 28.850 29.374 29.324 27.729 26.637 28.175 27.491 27.471 26.567 26.349 26.763 7. C7l 6.375 5.183 5.320 I1.847 4 .211 5.070 9.273 9.7,13 10.065 11.150 12.149 12.067 12.199 13.568 14.549 13.985 12.669 13.551 13.185 1-.408 12.034 11.293 14.909 15.106 15.789 16.983 17.607 16.503 18. 411 17.950 19.060 17.777 18.809 20.011 21.174 22.444 23.376 23.608 22.929 24.543 18.328 17.381 18.809 18.385 17.008 16.306 16.560 15.371 15.721 1.335 14.332 13.337 12.273 10.967 11.140 10.237 8.872 11.928 12.179 11 .423 11.107 12.085 11.653 12. 912 12.726 13.503 14.695 1" .925 9.738 9.611 8.754 7.376 6.461 5.021 7.012 .250 6.959 .182 .199 7.103 8. 4.13 8.402 9.840 10.662 11/58 73. 018 73. 165 ,3.2418 74.413 75.621 75.8000 76.577 .5.10 12.223 70.637 70.590 69.310 69.050 71.721 71.756 71.127 72.649 68.576 67.469 66.307 65.374 65.558 64.643 68.009 68.243 68.350 69.145 69.579 69.738 70.855 68.332 68.831 67.019 66. 180 65. 951 65.543 65.529 64.451 63.266 62.868 62.494 6-1.78 .1 64.430 64.284 62.983 63.001 64.006 61.894 61.833 61. 223 60.957 60.687 60.557 59.771 60.591 62.036 60.684 61.407 58.521 59.532 57.501 56.247 55.169 53.816 52. 992 51.770 50.720 50.696 49.789 15.791 55.406 5S.886 55.555 56.760 56.449 57.874 59.176 5.1.398 54.664 53.190 51.935 51.216 49. 969 49.578 50. 414 1.00 1.01) 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00I 1.00 i.00 1.00 1 .00 1.130 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1 00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 00 1.00 1.00 1.00 1.00 1.00 1 00 1.00 1.00 1.,0, 1 00 1.00 1 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1 .00 1.00 1.00 1 .00 1 .00 100 1.00 38.11 48.37 50.71 52.38 72.73 81.87 78.27 32.58 39.89 33.47 30.97 31.00 37.79 12.28 24.93 38. 14 35.96 31.90 23.39 16.51 20.38 18.30 25.48 27.40 32.86 30.43 28.27 35.78 40.26 28.13 27.95 32.99 30.28 31.25 25.13 30.68 17.12 33.40 46.41 40.30 39.82 31.50 32.67 32.60 28.87 32.32 38.03 34.11 36.71 15.32 32.12 34.11 26.55 32.90 38.07 34.05 26.54 27.11 33.98 32.15 30.54 27.48 26.35 25.83 32.92 50.34 47.61 44.92 46.00 29.74 36.52 33.99 36.26 33.27 15.85 31. 92 42.3.1 39.26 50.72 35.86 38.76 25.58 27 97 36.85 45.57 -AAA C AAA C AAAA C AAAA 11 AAAA C AAAA 11 AAAA 11 AAAA C AAAA 0 AAAA 11 AAAA C AAAA C AAAA O AAAA C AAAA C AAA 0 AAAA II IVAAA li AAAA C AAAA C AAAA C AAAA C AAAA C AAAA C AAAA O AAAA II AAAA C AAAA C AAAA 0 AAAA C AAAA C AAAA 0 AAAA 11 AAAA C AAAA C AAAA C AAAA C AAAA II AAAA C AAAA II AAAA II AAAA C AAAA 0 AAAA 11 AAAA C AAAA C AAAA 0 AAAA 1 MMN I-I AAAA C NAAA C AAAA C AAAA 0 AAAA 11 AAAA C AAAA C AAAA C AAAA C AAAA C AMAW I AAAA C AAAA C AAAA C AAAA C AAAA C AAAA C AAAA C AAAA 0 AAAA C AAAA C AAAA C AAAA C AAAA C AAAA li AAAA C ,%AAA C AAAA H AAAA C AAA C AAAA C AAAA O AAAA I11 AAAA C A.AAA C AAA AAC AAAA C AAAA O FAMA II AAAAW C AAPAA C AMAL C WO 99/28347 PCT/AU98/00998 12/5 8 ATOH 1134 022 GLU 1141 25.781 10. 1 C6 40 18 8 u 30 553 AA ATOMl 1135 C G, LU 114 280.03 9 6.072 50 9 44 1.00 44.17 TkkA C ATOMl 1136 0 G LU 114 29. 120 S. 538 51.090 1 .00 4 9.-97? TtAA ATOM 1137 1- LYS 115 27.191 5.,S56 S0. 096 1 .00 40.55 AAAA 1! ATOH 1139 CA LT S 115 2 7 219 4 .440 -49.2.2 1 .00 4 1 .16- AAA C ATOM 1140 CB L"YS 115 27,275 4 .7454 .17.71!8 1.00 23.62 AAA C ATOM 1141 CG LY,.S 115 27.019 A. 194 .17.411 1.00 18. 39 AAAA C ATOM 11,42 CD LYiS 115 26. 537 6. 355 15.982 1 .00 24 .74 AAAA C ATOll 1143 CE LYS 115 26.751 7. 804 4.1 .622 1.00 41.86 AAAA C ATOM4 1144 W' LYS 115 27. 165 8. 045 -14.196 1.00OC 60.91 ~AZA 11 ATOM 1148 C LY S 115 28. 287 3.421 49-.611 1.00I 42. 39 ?A.AA I ATOM 1149 0 LY S 115 29. 102 3.103 48 .7419 1.00 46G. 68 AAAA 0 ATOll 1150 11 ASH 116 28. 137 2. 677 50.665 1.00 40. 99 AAAA 11 AToll 1152 CA ASH 116 2 9. 022 1.570 50 .97 6 1.00 37.33 AAMA C ATOH 1153 CB3 ASHI 116 29.5341 1.868 52. 381 1 .00 46.12 AAAM C ATOll1 1154 CG ASH 116 30. 372 3.153 52.3415 1 .00 4S. 92 AAAA C AT011 1155 001 ASH 116C 31.337 3.016 51.583 1.00 38.59 AAAA 0 ATOM 1156 1102 ASH 116G 29. 927 4.174 53.056 1.00 37. 35 MAAA 11 ATOl 1159 C ASI 116I c 28.2-75 0. 277 50. 974 1.00 42. 52 ?AAA C ATOl 1160 0 ASI 116 c 28.067 -0.361 52. 033 1 .00- 48. 24 AAMA 0 ATOM 1161 HI ALA 117 27. 989 -0.188 49.772 1.00 40.94 AAMA It ATOl1 1163 CA ALA 11-7 27.195 -1I. 37 6 49. 542 1 .00 4 3. 35 AA C ATOM4 1164 CBI ALA 11-7 27.494 884 48. 156 1.00 47. 63 kAAA C ATOM~ 1165 C ALA 117 27.294 -2.504 50. 529 1.00 46C. 55 AAAA C ATOI 1 1166 0 ALA 117 26.211 998 50.890 1.00 51. 24 TAAAA 0 ATOH~ 116C7 I1I ASP 118 28. 484 -2.823 51.005 1.00 47 .43 AAAA H ATOM 1169 CA ASP 118 28.559 -3.980 51.920 1.0 CO15.741 AAAA C ATOM 1170 CB ASP 118 29.659 -4.9415 !51l.477 1.00 55 .39 ARAA C ATOM 1171 CG ASP 118E 2 9.6Go84 1!9 19. 958 1 .00 40 ~AA C ATOll 1172 001 ASP 118 28. 8'?0 5. S76 -19.-608 1.-00 64.10- -A;A ID ATOf 1 1173 002 ASP 118 30. 4 48 -4.447 419.207 1.00 G66. 73 ?IAPA 0 ATOM 117.1 C ASP 118 28. 818 586 53.353 1.00 37 .29 AJ\ C ATOl1 1175 0 ASP 118 2 9. 127 -4.536 54.026 1.00 42.89 AAAA 0 ATOM 1176 11 121' 119 28.670 -2.327 53.685 1 .00I 36.46 AAAA I I ATOM 1178 CA LELO 119 28.986 -1.885 5E. 04 7 1 .00 40.58 AAAA C ATOM 1.179 CB LELO 119 29.159 -0.389 SS. 14-5 1.00 34 .31 AfvAA C AToll 1180 CG LELI 119 29.640 0.331 56 3 78 1.00 36.58 AiA C ATOll 1181 CDl LEU 119 30.950 -0.101 56. 948 1.00 35.77 AAAA C ATOMl 1182 CD2 LEL' 119) 2 9.7 91 1.830 56.104 1.00 29.68 AAAA C ATOMl 1183 C LEII 119 27. 937 -2.376 56.007 1.90 4 3.6G7 AAAA C ATOl 1184 0 LEO 119 26.748 -2.248 55. 7 43 1.00 4 5. 32 AAAA 0 ATOl 1185 14 CYS 120 28.361 967 57.110 1.00 43.53 AAAA I I ATOll1 1187 CA CYiS 120 27. 378 -3.407 58.089 1.20G 38. 93 AAPJ\ C ATOll 1188 C CYS 1210 27 .881 -2.921 59.426 1.00 41. 91 AAAA ATOl 1189 0 CY S 120 28. 660 -1.960 59.446 1.00 43.66 AAAA 0 ATOll1 1190 CB CYS 120 27. 2 8 4. 907 58. 100 1.00 37.5E9 AAAA C ATOll1 1.191 SG CYS 12 0 26.568 -5.622 56 .639 1.00 58.3 2 AAMA S AT01ll 1192 11 TYR 12 1 27 328 -3.456 60.5109 1.00 38. 05 AAAA 11 ATOll 1191 CA TYR 12--1 27.795 -3.010 61.927 1.90 39.68 .MAA C ATol1 1195 CBI TYR 12- 1 2'-9.18 9 -3.572 C2. 13-- 1.00 34.61 A.MA C ATOM 1196 CG TYR 121 28. 950) -5.032 6-2. 519 1.00 36.52 APA,\ ATOll 1 197 C M TYR 12 1 29. 087 -6.0C4 5 61 .582 1 .00I 33.58 A ATOll 1198 CEl TY R 121 2 8. 85 -7.350 61.980 1.00 41.21 AAAA C AT01ll 1199 CD2 TYR 121 28. 560 -5.337 63.817 1.00 36.31 AAAA C ATOll1 1200 C E2 ri: 121 28.257 -6.630 64 201 1 .00 r 39.48 AAAAC ATOll1 1201 C7 TlYR 12 1 28.432 -7.641 63.270 1.00 4 6. C- 1AA AToll 1202 OH TYR 121 28.161 924 63.730 1 0C 4 9. 20 C ;AAA 0 ATOMl 1204 C TYR 12--1 2 7.6C171 523 61 .789 1.00 38.83 AAAA ATOl1 12'05 0) TYR 12111 28. 445 -0.778 62.369 1.00I 43.22 AAMA 0 ATOl1 12 06 11 LEII 122 26. 587 04 5 61. 16J 1.00 39.59 -aAA 11 ATol 1208 CA LEU 122 26. 361 0.405 C-1.-090 1.00 4 4. 82 AAAA C AToll1 1209 CB LEO 12 2 25.990 0.715 59.6C34 1.00 46.48 AAMA C ATOl1 1210 CG LEU 122 26.497 2.014 59.108 1.00 44 .44 AAAA C ATOMl 1211 CDl LELO 122 25.778 2 .448B 57.859 1 .00 32.19 AA. C AT01l1 12127 CD2 LEOI 12 2 26.136 3. 051 6,0.170 1.00 47.76 AAA C AT Ofl 1213 C LEt' 122 25.212 0.910 61.935 1.00 44 .85 AAAA C AToll1 1214 0 LEO 122 25. 269 1 .759 62. 839 1 .00 47.66 AAAA 0 ATOM 1215 1.1 SER 123 2111 0.137 61.843 1 .00 40.12 MAAA If AToll 1217 CA SER 123 22.-94 9 0.435 62.703 1.,D0 33.88 iiAAA C AToll 1218 CB SER 123 21.75.1 -0.330 62. 239 1 .00 19.26 AAAA C AToll 1219 0.3 SER 123 21 .961l -1.762 G2.402 2.00O 34 .35 AAA.A 0) ATOl1 12 21 C SER 1 2 3 23.165 0.060 64.159 1.00 37 .43 -AAA C7 ATOMl 1222 0 SEP 123 22. 326 0.28 6e) 5 025 1.00 35.33 MMA 0 ATOM 1223 11 THR 124 24.242 -0.698 G4.432 1.00 39.03 ;%AAA 11 AToll1 1225 CA THllR 124 24. -554 -1.165 C5.753 1.00 37 79 zjA ATol 122- Z6 CB TH R 1211 25.369 -2.461 65.719 1 .00C 42. 39 PAAA AToll1 12:27 001l TIIR 1 2 4 26. -502 -2.020 64.924 1.00 47.70 AAA ATOll 1229 CG2 THR 12Z4 24.677 622 65. 006 1.00I 40. 93 AAMA C ATOll1 1230 C T14R 11 25.522 -0.206 66. 14 5 1.00 39.29 AAAA ATOll1 1231 0 THR 12-I 25. 9.18 -0.642 C,7-199 1.00 41.41 ;.AAA 0 AT01l1 1232 I VAL 125 5.737 1.001 65. 985 1.00 37.80 AAA H ATOll1 1234 CA VAL 1 2 5 -26.5-191 1 .9QC4 6 661 1.0 1 OC AMAAC ATOll1 123 5 CO VAL 12-5 27.-683 2. 542 65.71 -1 1.00 39.5,0 kAA c ATOll1 1236 CGl VAL 125s 28. 570 3.599 6C. 3S' 1.00 28.36 :AAA AToll1 123-7 CG2 VAL 125S 28.693 1.565 65. 110 1.00 33.07 AM7AAC WO 99/28347 PCT/AU98/00998 AT C1 I ATrOi AM Il ATO; I ATOMl AToll1 AT0ll

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ATMI

ATOI I AT01 I ATOI I AT01 I 1238 1239 12420 1243 12.14 1245 12 '16 1247 12418 124.9 1251 12521 1253 1.254 12558 12 17 1258G 1260 1261 1262 12637 1268 1269 1271 1263 1276 1 -2-7 1-"72 1 16 1281 282 1284 1285 1286 12897 1288 1 289 1290 1291 1293 12-94 12 95 11-296 1 2 7 1298 1299 1300 1302 1303 130C4 1305 1306 1307 1308 1309 1311 131 2 1313 1314 1315 1 317 1318 1319 1320 1321 132 2 132 3 132 5 1326C 1327 1329 1330 1331 1333 334 1335 1 '.75',1 24 941 26.072 25. 310 24.86C2 23. 8 79 2 3. 6 99 23.220 26. 14 '6 26.740 26.029 26.777 26.568 27.195 28.587 28.631 29. 778 2 6. 4 65 27.311 2 9. 7 92 3 0. 972 30. 937 26. 558 27. 382 25.493 25. 201 2 3. 757r 23.433 26. 133 26.212 26G. 662 27.701 27. 920 26.795 27.292 26.232 29. 054 29. 645 29. 31C 30.480 30.793 31. 992 30. 969 31.053 30.305 31.224 29.089 28.895 28.499 28. 023 29. 128 27 .661 26.599 26. 610 27.017 27.349 27 536 27.413 2 5.5 2 0 24481 25. 75.1 24'1.9.17 25.6213 24 694' 24 77 7 24.115 23. 813 23. 202' 24.265 22. 616 21. 920 880 20.093 2-0.882 21. 39C 22.61IS 298 -4 .324 23. 724 .3 127 3. 7 SCO 3.6f:36C .1.734 .335 5.303 C. 520 4.865 S985 A. 400 ;64.9 7. 856, 8.296 7. 37 2 7.208 G.3186 .845I C6. b15 5.712 S..7 83 71.445 6.405O 9.010 9. 977 8.931 10. 041 10.0,12 8. 912 9.971, 10. 857 P. 7 92 8. 607 7.132 324 5.02-1 7 11'7 9.22C 10.001 9. 217 9.743 8.886 9.4'34 7.413 6.457 11. 178 11.985 11 495 121.96C5 12 .116 12.805 13. '581 1 3. '25 12. 867 14 .811 15. 54 2 16. 9'44 12.137 16. 122 18. 331 IS. 659 IS. 032 16.398 16. 776 987 15.669 15c. 7 91 14. .565 13.440 1 .7 01 13.732 13. 10C, 14.7 77 15. 139 16. 277 17. 369 15. C-1 2 15. 111 16.353 103.709 13/58 31 6.8 367 618. 967 10. 342 983 70. 685 71. 9641 68.872 67.704 67 4 10 6 5. 93 0 64..907 6 4 5 18 C63. 5 79 r64 .873 6 4.18 8 C3.3941 62. 954 C4.285 C3. 336 68. 367 68. 4971 69. 171 70.081 .10. 603 71.424 72. 134' 71. 54 9 2. 741 73.371 73. 975 '74 .5C-) 72.113 72. 824 70. 807 70. 141 68. 901 68.176 69. 347 68. 165 69.679 69. 966 69. 193 68.6c51 67 .259 6,5.878 15. 32 4 6S. 334 6.9. 285S 69. 311 69. 518 70. 003 7 0. 381 /1 .834 72. 521 72.208 68. 946 68 .939 67. 90() 66. 773 66l.092 G S. 7 7 6.1 517 6-6. 219 CS. 377 66. 120 66.85S r7 0G8 6-1 .353 C63. 292 64.626 6 3. 692 C-1 305 34 684 C2 .309 61. 359 6 2.1I C.

y. 979 61l 3,9 61 7i- I 00O 1 .00 1 .0 I 00 1 CI0 1.00 1 00 1 .00 1.00 1.00 1.00 1 .00 1 .00 1 .00 1.00 1.00 1.00v 1 .0C0 1.00 I 00 1 .00 1.00 1 .00 1 .00 1.00 1. 00 1 00 I .00L 1 .00 1 .00 1 .00 1 00 1.00 1 .00 1.00 1.00 1. 00 1.00 1.00 1 .00 1 .00 1 .00 1 .00 1.00 1. 00 1 O0 1 .00 1.900 1.00 100 1 00 1 .00 1.00 i.00 1 .00 1 00 1 .00 1 .00 1 .00 1 00 1.00 1.00 1 00 1 00 1 .00 1 .00 1 .00 I 00 1 .00 1 .00 1 00 1 .00 1. 00 C- '0

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.11 .22 37. 41 34 .73 415.53 27 .71 52 .32 40.83 42. 78 35. 42 33. 02 2.89 31. .3C 28.60O 2.9. 06 35.51 1 8. 67 42. 87 32. 53 31 5I 37 .86 36.09 40. 87 31 24 34 .04 36. 87 28.96 32.39 30.91 2.18 36.73 32.53 39. 28 32. 54 32. 12 38.04 34.50 42. 09 41.35 41.73 31.95 26.64 4 2. 65 46. 48 38.46 -15.14I 41 45 46.81 36.79 30.I1S 19.92 39.292 37 33.73 38. 20 4 3. 17 43.29 4 7. 12 60. 5; 413. 46C 49.32 45.03 38.62 33.82 33.33 33.71 27.88 29. 90 40.63 35. 2C 30. 8.1 36.98 32. 9S 39.65.

43.12 45.19 39.25 41. 15 43.81 41.11 37. 39.6C1 36.59.- -,AAA C2 AAAA AAAA CI AA C A.M.A C A.M.A 0 AAAA 0 AAAA C AAAA 0 AAAA 11 AAAA C AAAA C AAAA C2 A.AAA '2 A.M.A C AAAA C2 AAAA C2 A.M.AA 2 A.M.A C AAAA C AAAA '2 AAAA 0 AAAA 11I AAAA C2 AAAA C2 A.M.A 0 AAAA C A.AAA 0 AAAA '1 AAAA '2 AAAA C A.AAA C AAAA C AAAA C2 AAAA 0 AAAA 0~ AAAA 1C AAAA C AAAA C AAAA C AAAA C AAAA C AAAA 0 AAAA 0I A.M.A '2 A.M.A C AAA C2 A.AAA '2 TtAA '2 A.M.A '2 AAAA 0

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AAAA 11 AAAA '2 AAAA C2 AAAA 0 A.M.A 0 AA AA 02 AAAA 0 MMA 0* AAAA H2 A.M.A '2 AAAA '2 AAkAA C AAAA II AAAA 11 AAAA '2 A.AA.A C AAAA '2 AAAA 11 AAAA CI AAAA C2 AAAA '2 A.AAA 0 AAAA AAAA 0- AA.M MM C2 AT01 1 1336 001 ASHI 136 22 .695 19. -07-19 1. 149 1 .30 50. 81 WO 99/28347 PCT/AU98/00998 ATOllI ATOI I IATOI I AT OfI ATo OIl ATOlM ATOllI AT 01 ATOMl ATOI I ATOIlI ATOI I ATOil ATOllI ATOI I AT OfI1 ATOll ATlOl I ATO OI ATOI I A TO I ATlOI ATOMl ATOI I ATOll ATOI I ATOlli ATOllI AT 01 ATOfll AT 01 ATOT I ATOllI ATOI l ATOll

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ATOllI ATOllI ATOllI ATOllI ATOllI ATO I1 ATOllI ATOI l ATOI I ATOM1- ATOI -I ATOllI ATOI I ATOll ATC'l 1 ATOI i ATOMl- ATOll ATOll ATOI I ATOl ATOI I AZTOI I ATOllI AT Oll ATOllI ATOllI ATOI I APTOI I ATOI I A'TOllI ATOI 0I 1337 1340 1341 13412 1344 1345 1 3 '16 13417 1348 1 351 1352 1353 1355 13.56 1357 1358 1359 1360 1361 136C 2 13C3 1365 1366 1367 13C9 1370 1 371 1372 1373 1374 1375 1376 1378 1379 1380 1381 1382 1383 1384' 1386 1387 1388 1389 1391 1392 1.393 1394 1395 1398 1399 1400 1402 1-103 14 0 4 1405 1406 140'7 1'1111 1412 1-I113 1411I 1415 1I .16 1417 1418 1-11 9 1,12 0 1421 1 -122 1423 14 2 4 14 '25 1426 1427 1.129 1430 1.131 1432 1.133 1434 1438 1-13 9 1440 144 2 1443 37 9 24. .031 24. 535S 2.1.7 2 1 24. 7 3 1 25.631 2).70 2830 23. 950 22.71C 24 .5'92 24.093 24. 682 N4. i'18 23.083 22. 51.0 24.357' 23. 8-1 2.868 22296 24.373 25. 505 23. -161 23.6G37 2 3. 23 -I 23.640 23. 711 24.45 7--q 538 23. 286 22. 533 21. 967 22. 800 20. 807 23.422 24.537 22.899 23. 381 24 .265 25.132 23. 985 24 85 8 25. 257 26. 131 26C,. 9 0-I 25. 945 24.153 23.113 24.1574 25. 166f 24 .75 10 25S. 5 12- 25. C.4 3 26. 080 22. 902 2 2. 960 806 2-1.6C17 20. 55 9 19. 54 9 20. 134 210. 521 2-0. 90-4 20. 318 2 0. 123 2-0.448 19. 70I 19.01'93 20. 556 18.870 16. 823' 14.7a'! 141. 14 7.-C 21.1-31 1 9.41 15'. 230 15. 484 1 4.035 12 .959 11.703 11.965 13.121 10. 923 12 74 9 12.755 12. 251 11.983 12.861 12.7'41 13.671 13.579 11 .717 11.615 1.2.562 12 .504 10.5178 10.317 9.660 8. 249 7.450 5. 984 8.057 7 .100 7.,708 7.80 6. 997 6.4-81 7 627 8.375 7 .034 5.670 6.172 4 .562 3.805 2.6C96 2.003 .418 1.390 1 .774 3.022 3.077 4 .022 -i .015 990 3 .32 8 -4 .686 -5.743 -7 .131 -B.093 -2.431 -2.099 -3.047 469 118 -3 .60O2 -3.299 -4 .050 -236 -3.533 -2 .054 i .233 I 910 -5.6C55 -6.592 924 I .229 -7 .050 -8.232 -8.422 3610 138 3.6 -7.64 9 4 4 C -8.070 14/5 8 6258b CC).259 59.-19i C60. 793 C60). 1261 61 033 62. 217 62. 369 63. 000 58.817 58.855 17 .785 56. 489 '55. 421 54.078 53. 3-18 52.392 53.195 5 1 0151 51 .5C4 '50. 318 56.0511 55.797 56.116 55. 935 5.171 57 .093 58.4(9 59. 389 54 930 54 .757 53 .873 52.755, 51 .881 50. 881 51 .047 51 .874 51.-637 51 .402 50.278 50.8B35 10.176 52 .116 52 .74C 54 .187 53 .269 55.019 52.687 S52. 055 53 .272 53.195 53. 433 53.8B32 5 3. 100 53.558 53.040 54 .169 5 5. 360 53.731 52 .315 5.1 .489 53.455 52 .099 5659 55 ',1 56.859 57. 09-I 8 128 59.099 58. 602 58 .155 58.768 57 .489 57 .295 56.6C4-1 S5. 982 56. 451 51.934 55.753 56'. 44 6 FC0. 7 3 2 55. 389 5 1 742 53.294 1 00 1 .00 1 00 1.-00 1 .00 1 .00 1.00 1 00 1.-00 1.-00 1.-00 1.-00 1 .00 1.00 1 00 1.00 1.-00 1 .00 1.00 1 .00 1 00 1.100 1 .00 1.00 1.00 1 0 1.00 1 .00 1 .00 1 .00 1 .00 1.00 1 .00 1.00 1 00 1.00 1. 00 1.00 1 .00 1.00 1 .00 1.00 1 .00 1.0 1.-00 1.00 1 .03' 1 .00 1.00 1.00 1.00 1 00 1 .00 1 .00 I1. .0 1 00 1 .00 1-00 1.00 1 .100 1.00 1.00 1 .00I 0 01l 47-.85 35.31 38.70 289. 11 32. 98 24 .45 26.63 3 0.2 18B. 90 35.89 38.57 32.86 30.2 27.10 3'7.8 9 39. 22 37.65 4 4 28 4 1.9 39.42 415.48 31.33 37.-76 35.40 34 04 28. 66 21. 99 42 .861 52.23 35.73 42. 61 35. 2, 9 32 .39 36.05 25.88 34. 96 41. 96 44 .03 42.66 30.94 38.98 35.871 38. 92 44 32 43.12 42.00 410.4.7 -111. 98 45. 84 4 9. C 4 5. 23 4 9. 14 41.49 4-I. 96G 48.66 38.35 53.83 52.85 55.21 52. 39 52.58 48.30 51 .41 50.41 44 .6C5 36.84 12- 38 0. 17 40.19 37.08 33.65 -17.1 7 48 05 53.7 6.94 6 5. 44 C4. .32 62. 75 G2. 14 61.38 61 4 l 6c. 22 62-I. 92 C7 3-2 62. 32 AAA AAAA C2 AAAA 0 A AI I AAAA C AAAA C2 AA\AA C2 AAAA 0 AAAA 1-i AAAA C2 A.AAA 0 AAAA 11 AAAA C2 AAAA C2 AAAA C AAAA C2 AAAA C AAAA '2 AAAA C2 AAAA C AAAA 0 AAAA C2 AAAA 0 AAAA N- AAAA C AAAA C AAAA '2 AAAA 'C AZAAA C LAAA C2 AAAA 0 AAAA 11 AAAA C AAAA '2 AAAA C AAAA C AAAA C AAAA 0 AAAA If AAAA C AAAA C AAAA 0 AAAA 11 AAAA C2 AAAA '2 AAAA C AAAA 0 AAA 11 AAAA ?AAAA 0 IIA 1

~AAC

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AA.AA

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WO 99/28347 PCT/AU98/00998 AT 044 ATO OI ATOI l ATOlI ATOll ATOMl ATOIl I ATOlM

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2224 ATOM1 2225 ATOM 2226 ATOl 222 7 ATOM 22 28 ATOM 222 29 AToll 2230 ATOMl 2232 AT01ll 2 23 3 ATOl1 2234 ATl 22)I1 3 5 AT0ll 2 236 A T'0ll 2238 ATOM 223 9 ATOM 2240 ATOl 2 2411 ATOM1 2242 ATOM 22413 ATO 0 2 244 ATOM 2245 ATOM 224 6 ATOM 2247 ATOM 2248 AT OM 1 22 49 AT01ll 2250 ATOM 251 ATOM 2252 AT01ll 2253 AT (Al 22514 ATOM 2 25 5 ATOM 22 56 AT01l1 2257 ATCll 2259 ATOM 2261O ATOM 2262l ATOM 22C3 ATOl 2 266 AT0ll 2267 AT01ll 2268 AT0ll 22-'7 0 AzT0ll 2 271 ATOM 227 ATOM 227 4 PCT/AU98/00998 22/58 2C6 50. 455 22. 313 '77 .785 1.00 22C 51 .71 23. 126 77.9.41 1.00 2126 52.121 2.3.557 79.197 1.00 226 53.289 24.275 719.400OC 1.00 226 52.580 23.409 76. 864 1.00 226 53.758 24.118 '17.020 1.00 226 54.099 241.549 -78.301 1.00 226 55.267 25.2541 78.43L 1.00 226 51.784 20.356 78.165 1.00 226C 51.492 20.133 79.350 1.00 '227 52.978 20.080 77.642 1.00 227 54.061 19.557 78.440 1.00 227 54.528 20.620 70.428 1.00 227 53.600 18.309 '79. 1'70 1.00 2 27 53.663 18.218 80.413 1.00 228 53.076 17.360 78.393 1.00 228 52.585 16.135 79.028 1.00 228 51.312 16.330 719.861 1.00 2728 51.028 15.538 80.776 1.00 229 50.643 17.495 '9.7 91 1.00 22 9 49.489 17.671 80.635 1.00 22-9 1.90c8 18.610 81.774 1.00 29 48.627 18.896 82.566 1.00 29 51.002 18.035 82.682 1.00 229 48.255 18.173 79.873 1.00 22 48.344 19.279 79.309 1.00 230 47.100 17.518 80.036 1.00 230 45.81 19117 79.471 1.00 236 .15 .4 E6 19'-.2350 19.226 1.00 230) 44.964 19.2-18 81.321 1.00 230 441.746 17.132 79.370 1.00 230 45.149 15.753 78.266 1.00 231 45.63-7 20. 534 -79. 731 1.00 231 45.445 21.769 80.462 1 .00 231 46.618 22.736 80.080 1.00 231. 46.798 23.878 81.053 1.00 231 47.838 21.913 80.506 1.00 231 44.111 22.321 80.057 1.00 231 43.599 22.183 78.936 1.00 232 43.482 23.105 80.913 1.00 232 43.830 23.385 82.320 1.00 2732 42.153 23.625 80.575 1.00 232 41.537 2'3.e77 81.928 1.00 232 42.683 24.287 82.765 1.00 232 42.361 24.913 '79.79S 1.00 22 41.498 25.482 79.137 1.00 233 43.C15 25.400 79.901 1.00 233 43.998 26.569 '79. 124 1.00 233 43.440 27.801 7 79. 74 C 1.00 '33 4 5. 5,-2 78.974 1 .0 0 23 46.195S 25.879 1'9-(6 1.00 231 45.Ge-4 27.508 ?8021.00 23.1 47 .430 27.S18 771.907 1.00 234 48.001 2 8. 34 0 7c. 076C 1 .00 234 47.650 29.513 79.2501 1.00 234 47.816 28.034 76c.511 1.00 234 47 .60C8 26. 78 9 75.226 1.00 -35 49.127 27.853 '79.599 1.00 235 49.692 26.557 207 1.00 235 49.911 28.569 80.599 1.00 235 50.984 27.581 80.975 1.00 235 50.912 26.417 80.077 1.00 "35 504729.852 80.050 1.00 23 5 50.8.18 29. 957 7 8 .8F70 1.00 236 50.676 30.875 80.887 1.00 236 50. 405 30.822 82.363 1.00 236 51.323 32.1413 80. 4 93 1.00 236 51.695 32.814 81 .8:6 1,.00 236 50.652 32.277 82-1. 75 1 .00 236 52.5415 31.886 79.671 1.00 236 53.215 30.892 '79.928 1.00 23 7 52.837 32.757 78.316, 1 .00 237 53.895 32.623 77 .71 1.I-C0 237 55.259 32 .6C53 78 4 5 1.00 237 55.3571 33.855 719.371 1 .00I 2'-37 5 6. 0- i 33.783 3 79 1.00 2371 54.631 34.910 '79.051 1.00 2 37 53.897 31.425 -76.788 1.00 2 37 54.962- 30.935 76C,.3 26- 1.00 238 52.617 30.657 70.692' 1.00 39 28.248 7.41 1 i..00 238 5127 28.3413 7 2 27 1 .00- 233 53 .5S52 .'7.986- 74 2 4 1.00 56. 83 59.511 65. 45 69.12 70.77 69.38 70. 94 72. 96 -70. 84 57 55 56. 90 53. 82 51.82 55.81 53.56 49.63 50.68 4 9. 02 51.61 51.10 47 .09 51.11 56.52 38.39 50.16s 51 .37 53.71 4.221 410. 32 38 .4 42 4 1. 62 31 .54 43.61 39.83 46.57 50.99 50.41 44 .95 52.59 55.30 54 .28 54 .25 54 .39 53.7'3 56. 37 55.7 9 54 .7( '19. 93 35.43 49.79 51.41 45.07 418.63 50. 93 .1 *7 57 43. 10 43.04 49.55 8.7s 51.69 50.80 50.06 57.11 59.60 59.85 55. 85 52.27 53.62 56.73 44 .21 43.40 46.541 4I5. 94 58.65 58.5'1 '72. 25 62.99 46.87 5: 50 42 91 0. 20 4~2. C62 34 .8 4 A 2AAr AAAA C AAAA C2 AAAA C2 AAAA C AAAA C2 AAAA C2 AAAA 0 AAAA C AAAA 0 AAAA 11 AAAA C AAAA C2 AAAA 'C AAAA 0 AAA 1 AAAA C AAAA C AAAA 0 AAAA 1! AAAA C2 AAAA C2 A.AAA C AAAA C AAAA C AAAA 0 AAAA 11 AAAA C AAAA '2 AAAA 0 AA.AA S2 AAAA Sf AAAA C2 AAAA C AAAA C2 AAAA C AAAA 02 AAAA 01 AAAA CI AAAA '2 AAAA C AAAA '2 AAAA '2 AAAA 02 AAAA 01

AAA

AAAA '2 AAAA C2

AAAA

AAAA 1: AAAA C; AAAA 02 AAAA 0 AAAA S AAAA If

AAA

AAAA C AAAA '2 AAAA '2 AAAA C2 AAAA 1C P.AAA 0 AAAA C AAAA AAAA A.AAA C AAAA 0 AAAA 0: AAAA 17 AAAA '2 AAAA '2 AAAA 0 AAA 11 AAAA C AAAA 0

IIAA

AAAA C AAAA '2 AAAA 0

AAA

WO 99/28347 PCT/AU98/00998

ATOI

ATOI I ATOll ATOll

ATOM

ATOHl ATO I ATOll ATOI I

ATOM

ATOM

ATOI I

ATOI

ATOHl ATOl

ATOH

ATOI I ATO I

ATOH

ATOll ATOI I ATOM1 ATOIl ATO I ATOll ATOI I ATOI I

ATOII

ATOI I ATOI I ATOI I ATOIl ATOll ATOI I ATOll ATOI I ATOll ATOI I

ATOH

ATOI I

ATOI

ATO I

ATOHM

ATOI I

ATOM

ATON

ATOI I ATO I ATOI I ATOI I ATOI I

ATOI

ATOI I ATOMl ATOMl ATOI I ATOI I ATO I ATOI I ATOll ATOI I ATOI I ATOI I

ATOH

ATOi I ATOll ATOI I ATO I

ATOM

ATOIl

ATOH

ATOI I ATOI I

ATOII

ATOl ATOl

ATOH

ATOll ATOI I ATOI I

ATO

ATOC

ATOi; ATOI I 2275 2276 2277 22/9 2280 2281 2282 2283 2284 2285 2286 2287 2289 2290 2291 2293 2291 2295 2296 2297 2299 2300 2303 2306 2307 2308 2310 2311 2312 2313 2314 2315 2316 2317 2318 2319 2320 2322 2323 2324 2325 2326 2327 2328 2329 2330 2332 2333 2334 2335 2337 2338 2339 2340 23-11 23-12 2343 2344 2346 2347 2348 2349 2350 2351 2353 2354 2355 2356 2357 2359 2360 2363 2366 2367 2368 2370 2371 2372 2373 2374 2375 2377 2378 2379 23/58 238 51.279 29.875 75.0!8 1.00 2.

23 50.669 30.864 75.500 L.00 42.51 239 51.051 29.488 73.832 1.00 42.62 239 49.949 29.959 73.024 1.00 41.87 239 50.457 30.907 71.931 1.00 44.86 239 51.099 32.125 72.561 1.00 12.05 239 52.467 32.086 72.815 1.00 39.41 239 53.092 33.152 73.415 1.00 43.27 239 50.376 33.230 72.923 1.00 44.15 239 50.972 34.310 73.536 1.00 46.22 239 52.339 34.243 73.779 1.00 50.49 239 53.013 35.289 74.387 1.00 55.47 239 49.232 28.813 72.315 1.00 15.54 239 49.922 27.810 72.021 1.00 46.66 240 47.895 28.990 72.126 1.00 410.62 240 47.177 27.892 71.426 1.00 38.78 240 45.675 28.127 71.452 1.00 39.77 240 45.116 28.944 72.588 1.00 43.37 240 4.13.573 28.957 72.683 1.00 38.60 210 43.114 29.683 71.455 1.00 53.98 240 43.123 31.015 71.530 1.00 48.07 240 43.513 31.562 72.668 1.00 47.65 240 42.788 31.778 70.533 1.00 51.03 240 47.627 27.737 69.979 1.00 31.72 240 47.937 28.730 69.302 1.00 32.37 2411 47.779 26.542 69.549 1.00 27.95 241 48.182 26.269 68.183 1.00 30.41 241 49.678 25.940 68.151 1.00 34.83 241 50.235 25.653 66.773 1.00 26.84 211 50.165 26.567 65.753 1.00 25.31 2-11 50.785 24.417 66.573 1.00 27.38 2.11 50.676 26.232 64.509 1.00 37.24 241 51.294 24.101 65.320 1.00 38.45 241 51.281 25.010 64.281 1.00 21.17 241 47.382 25.089 67.621 1.00 35.77 241 47.543 24.013 68.186 1.00 36.77 2-2 46.738 25.301 66.468 1.00 32.30 242 45.964 24.269 65.805 1.00 35.43 242 46.953 23.144 65.472 1.00 37.98 242 47.867 23.415 64.314 1.00 38.63 242 47.207 23.965 63.075 1.00 39.27 242 46.380 23.205 62.517 1.00 412.79 242 47.354 25.109 62.626 1.00 36.36 242 44.752 23.771 66.600 1.00 34.36 242 44.390 22.611 66.511 1.00 28.53 243 44.135 24.589 67.449 1.00 36.94 243 43.048 24.154 68.303 1.00 34.57 243 43.428 23.107 69.319 1.00 37.76 243 42.474 22.473 69.746 1.00 43.00 244 44.637 22.636 69.611 1.00 39.53 241 144.797 21.536 70.566 1.00 40.85 244 44.774 20.271 69.764 1.00 26.76 244 46.C12 19.885 69.028 1.00 43.19 244 47.019 18.983 69.498 1.00 39.55 244 47.998 18.906 68.489 1.00 36.50 244 47.186 18.254 70.692 1.00 32.18 244 46.421 20.308 67.779 1.00 43.37 244 47.595 19.727 67.469 1.00 38.89 244 49.150 18.128 68.620 1.00 39.01 244 48.336 17.478 70.815 1.00 43.98 244 49.322 17.425 69.784 1.00 42.50 244 45.998 21.517 71.509 1.00 42.98 241 46.253 20.501 72.146 1.00 42.70 2 5 46.888 22.485 71.435 1.00 44.16 245 48.160 22.472 72.095 1.00 46.47 245 49.203 21.602 71.367 1.00 47.30 245 49.985 22.309 70.203 1.00 4.8.97 245 51.129 21.552 69.819 1.00 39.28 245 51.586 21.665 68.444 1.00 50.86 215 52.629 21.044 67.895 1.00 46.73 215 53.344 20.236 68.653 1.00 50.15 53.072 21.126 66.638 1.00 41.69 2I5 48.771 23.863 72.271 1.00 46.01 2S5 48.394 24.793 71.541 1.00 47.44 "46 49.625 23.881 73.317 1.00 42.08 246 50.246 -5.199 73.628 1.00 43.48 246 51.695 25.217 73.183 1.00 -13.38 '46 52.476 24.239 73.320 1.00 42.51 216 50.102 25.392 75.138 1.00 48.91 246 48.386 25.049 75.797 1.00 43.68 27 52.121 26.288 72.564 1.00 41.21 147 53.417 26.468 71.982 1.00 36.51 7 53.569 26.357 70.444 1.0 36.87 247 53.089 24.988 '0.02 1.00 32.-1 24 53.129 27.602 69.729 1.00 28.2 mAAA C AAAA O AAAA ii AAAA C AAAA C AAAA C AAAA C AAA C AAAA C AA4AA C AAA O AAAA C AAAA O AAAA II AAAA C AAAA C AAAA C AAAA C AAAA C1 AAAA C AAAA N AAAA 0J AAAA C AAAA O AAAA II AAAA C AAAA C AAAA C AAAA C ,AAA C AAAA C AAAA C AAAA C AAAA C AAAA 0 AAAA II AAAA C AAAA C RAAA C AAAA C AAAA O AAAA O AAAA C AAAA O AAAA 0 AAAA CI AAAA C AAAA C AAAA II AAAA C AAAA 0 AAAA C AAAA C AAAA C AAAA C T"VV AAAA C AAAA I AAAA C AAAA C tAAA C AAAA C AAAA O AAAA I AAAA C AAAA C AAA C AAAA C AAAA II AAAA C AAAA II AAAA I1 PAAA C AAAA O AAAA II AAAA C AAAA C AAAA 0 AAAA C ,AAA II AAAA C AAAA C AAA C AAAA C iAAAA C ATOll 2380 CG2 VAL WO 99/28347 PCT/AU98/00998 ATCOi I ATO! I ATOllI ATOI I

ATOM

ATol

ATOH'

AToll ATOl

ATCVI

ATOI I ATOI I AT OI ATOI I AT Oi

ATOII

ATOI I KaTO I ATOil AT 01I ATrom~

ATOM

ATOll ATOll AT Oi

ATOM

AT Oi ATOil ATO! I ATOl ATOll ATO! I AT0O1l AT 01- ATOll1 ATOil ATOMl ATOil ATOllI ATOll ATOil ATOM4 ATOllI ATOll AT0ll ATOll ATCll ATOI l ATOll ATOI l ATOMl AT01ll AT01ll AT01 l ATOI I ATollI ATOllI AT01ll

ATOM

ATOlM AT01ll

ATOM-

AT01ll ATollI ATOI I AT01 I ATOlI ATOI I ATOI I

ATOMI

AT01ll

ATOM-

ATOll ATollI AT01ll ATroi I ATOlI ATOllI AToll ATOll ATOMl AT'OlI ATOll AT01lI ATOlM 2381 2382 '383 2385 2386 2387 2388 2389 2390 2391 2392 2394 2395 2396 2397 2398 24100 2 '101 2404 2410'7 2408 2409 2411 24 12 24 13 2414 2415 24 17 24 18 2421 2423 2424 2425 2 42 6 2427 2428 2429 2430 2432 2433 24341 2435 2-136 2.137 2439 2440 2441 2442 2443 2 4-15 24 46 2 147 2448 24 4 9 2452 2453 2454 245'6 2457 2458 2459 24C0 2461 2 462 2463 2465 24C6 2-1G7 2468 2469 2.470 2 47 1 2.17-2 2474 2.-1-75 2 4 76 2478 2.479 2480 2482 2483 2 48 4

'AL

VAL

ASP

ASP

AS P AS P

ASP

AS P

ASP

AS P

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARI'

ARG

AS P

ASP

AS P AS P AS P AS P AS P AS P PHI7 EIIlE

PHE

PHlE PHlE

PHE

PilE

PHE

PHlE

PHE

T HE

CYS

075 CY S 075 075

CYS

ALA

ALA

ALA

ALA

ALA

ASH

ASH

ASI I

ASI

ASH

ASI I

ASHI

ASII

I LE I LE

ILE

I LE

ILE

ILE

ILE

ILE

LEU

LEU

LEO

LEU

LELI

LEI

LEU

LEU

S 17R

SER

SER

SER

SER

SER

ALA

ALA

ALA

ALA

53. '69 53 .230 5529 F5.895 57 .091 58. 126 59. 067 58.167 56. 315 56.292 56.545 56 .950 5 7. 22 3 57.594 57 .814 56.658 55.0G32 55.642 54.0(41 58. 13-1 58.086 59.149 C0. 287 61.740 62.421 63 .124 62.272 59. 881 GO1.291 59. 116 5 8. 457 57. 4C8 506.701 57.101 55.559 56. 414 541.847 55. 294 57.624 57.811 56.731 55.895 56. 827 56.552 54 903 53. 562 57.8'72 58.6C87 59.s529 00. 147 ID9 6517 60. 5416 63. 468 C2. 607 59. 907 00. 552 58.6G12 57.828 56.329 55. 477 55.778 54 .479 58 127 58. 196 58. 290 58.680 58. 175, 56. 671 56. 310 55.965 G0. 193 CIO. CO91 6 0. 942 C2. 352 C2 .924 63. 381 60'. 973 C-4.127 033 62 57C3 24/58 28,770 /12.5'40 '27.820 72.711 201573.098 28.94C6 73. 953 271.997 13.394 27.795 74.187 27.395 72.313 29.883 71.839 29.288 70.772 31.163 71.918 32.057 70).900 33.485 71.491 34.42.1 70.326 35.811 70.843 36.150 71.689 36.823 71.101 37.118 69.801 37.118 71.9'16 31.685 '10.010G 31. 923 68 .7 97 30.974 70.408 30.739 C69 606C 30.726 70.154 32.122 70.081 32.682 69.17r, 32.928 71.071 29.536 68.771 29.443 A; .610 2 8 .60S9G 0. 299C 2-.601 68 489 26.7456 09. 2 5 25.80! A8.385 2.1.479 68.,263 26.1113 67.606 23.597 G7.424 25.

37 2 66.856 24.070 66.715 28.290 67.338 28.010 66.144 29.225 67.713 29.870 66.728 30.598 65.747 30.534 64.536 30.7'78 67.379 31.5,44 C6.459 31.256 66.285 32.071 65.415 33.088 66.172 31.10A7 5-1 .539 31.?35 G3 .640C 69.859 64.707 2 9. 073 63.920 28.4091 6..84-7 29.635 65.031 29.8-10 64 .081 30.321 66.14.1 27.95c- C3.135 26.965 62.804 28.13C 02."76 27.1071 62.131 27.322 C2.304I 26.595 (1.246 26.675 63.553 27.317 C .1 000) 2C.886 00.51 25.70Q 0,0.252- 27.900 S9.918 27. 76-i 58.10 29.C12 L7.799? 29. 19; 57.86.1 30.654 517.045 28.222 5(.928 27.622 58.355 27.511 57.24S 27.559 S9.430 27.529 59.53-1 27.318 W0.955 §790 GI1('7 I 2C.. 4 97 58 .010 c 2(.731 59. 2.1IS 25.399 320, 24.488 S 7 .3.13 Z3.039 57.56-Ij 24.9C4 55.921 1.00 39 37 1.00 38. 80 1.00 1l5.21 1.00 40.i9 1.00 42.63 1.00 58.81 1.00 53.06 1.00 C9.51 1.00 36.99 1.00 39.70 1.00 30.72 1.00 36.17 1.00 21.29 1.00 24.96 1.00 21.23 1.00 39.75 1.00 39.35 1.00 25.41 1.00 44.04 1.00 40.63 1.00 44.79 1 .00 41.87 1. 00 46. 90 1.00 53.11 1.00 71.49 1.00 58.53 1.00 70.30 1.00 41.22 1.00O 39.06 1.00 36.13 1 .00 34 .88 1.00 29.82 1.00 4 1. 50' 1.00 30.66 1.00 37.78 1.00 29.30 1.00 36.09 1.00 36.21 1.00 39.28 1.00 30.27 1.00 35.13 1.00 38.80 1.00 44.73 1.00 43.20 1.00 35.65 1.00 39.03 1.00 41.53 1.00 40.39 1.0'0 3C.07 1.00 42.88 1. 0) 47 .4 2 1.00 38.7S 3.00 42.94 1.00 48.09 1 .00 49.54 1.00 61.38 1.00 48.38 1.00 53.72 i.7-0- 51.19 1.00 57.77 1.00 53.28 1.00 50.41 1.00 51.95, 1.00 40.59 1.00 38.97 1.00 52C 1.00 53.96 1.00 .19.90 1.00 63.68 i.00 516.80, 1.00 59.11 1.00 43.31 1.00 55.88 1.00 66.23 1.00 _70c.29 1.00 6-1.61 1.00 69.23 1.00 62.45 1 .0CI 56.18 1 .0 70.777 1.00 72.50 1.00 7,1.61 1.00 76.34 1. 00 80C. 82- 1.00 78.21 '7 AAAA 0 APAA1 AAAA C ?AAA C AAAA C AAAA 0 AAAA 0 AAAA C AAAA 0 AAA 11 AAAA C AAAA C AAAA C AAAA C AAAA 11 AAAA C AAAA 11 AAAA 11 ?AAkA 0 AAAA i0 AA4AA C1 AAAA C AAAA C AAAA 0 AAAA 0 AAAA 0 AAAA 0 AAAA 0 AAAA C AAAA C AAAA C AAAA C AAAA C AAAA C AAAA C AAAA C AAAA C2 AAAA 0 AAA 11 AJ\AA C AAAA C AAAA 0 AAAA C AAAA S

AAA

AAAA C AAAA C AAAA C NA.A 0 AAAA '7

AAAAC

?.FAC

AAAA 0 A.AAA C) AAAA 0 AAAA i1 AAAA C AAAA C AAAA C AAAA C AAAA C AAAA C .\AAA AAAA C AAAA C AAAA C7 AAAA C AAAA C AMAA C AAAA 0 AAA !i AAAA C AAAA C AA-.-A 0 kA.AA C A-RAA 0I AAAA C

AAA

WO 99/28347 PCT/AU98/00998 25/58 ATOI 2485 ALA 258 62980 24.139 55.02 1.0) 79r60 AAA O ATOM 2486 II LU 259 62.069 26.109 55. 651 .00 79.05 AAkA ATOI1 2488 CA GL1 259 61.742 26.621 54.3, 1 .00D 83.84 AP.AA ATOII 2489 C 1 GLU 259 60.2:6 26.457 5 .1.135 1. 0 86.99 AAAA C ATOil 2490 C, GLU 259 59.687 5.-049 54.314 1.00 89.38 AAAA ATOl 2491 CD GLU 259 58.364 25.032 55.057 1.00 97.77 APA 2 ATOM 21492 OEl GLU 259 58.080 24.088 55.838 1.00101.45 AAAA C' ATOH 24I93 OE2 GLIU 259 57.598 26.002 51.837 1.00 94.58 AAAA O ATOM 2494 C GLU 259 62.117 28.078 54.083 1.00 85.43 AAAA C ATOH 2-195 O GLU 259 62.059 29.009 54.903 1.00 88.01 AAAA O ATOM 2496 11 SER 260 62.298 28.338 52.799 1.00 84.66 AAAA 11 ATOM 2498 CA SER 260 62.725 29.625 52.254 1.00 84.03 AAAA C ATOM 2499 C SER 260 63.753 29.269 51.173 1.00 87.24 APAA C ATOl1 2500 OG SER 260 63.306 29.419 19.835 1.00 93.65 AAAA O ATOH 2502 C SER 260 61.558 30.466 51.789 1.00 80.84 AAAA C ATO-1 2503 O SER 260 61.496 30.889 50.635 1.00 81.31 AAAA 0 ATOM 2504 11 SER 261 60.617 30.785 52.685 1.00 78.56 AAAA 11 ATOM 2506 CA SER 261 59.423 31.540 52.308 1.00 72.13 AAAA C ATOM 2507 CB SER 261 58.179 31.297 53.170 1.-0 67.30 AA C ATOM 2508 O SER 261 57.436 30.334 52.451 1.00 74.7-1 AAA C0 ATOM 2510 C SER 261 59.683 33.032 52.318 1.00 66.90 AAAA C ATOH 2511 O SER 261 60.018 33.588 53.334 1.00 63.24 AAAA O ATOl 2512 M ASP 262 59.364 33.659 51.204 1.00 65.30 AAAA 11 ATOMI 2514 CA ASP 262 59.358 35.071 50.915 1.00 58.55 AAAA C ATOl 2515 CB ASP 262 59.268 35.285 19.400 1.00 64.85 AAAA C ATOM 2516 CG ASP 262 59.389 36.713 48.931 1.00 76.42 AAAA C ATOl 2517 0D1 ASP 262 59.473 37.708 49.701 1.00 79.81 AAAA 0 ATOM 2518 OD2 ASP 262 59.404 36.873 47.671 1.00 80.46 AAAA O A poii 2519 C ASP 262 58.121 35.706 51.529 1.00 56.88 AAAA C ATOM1 2520 0 ASP 262 57.851 36.918 51.510 1.00 52.4 AJAAA C ATOMH 2521 I SER 203 57.259 34.8 49 52.118 1.00 53.13 AAA 1! ATOl 2523 CA SER 263 56.047 35.35252.734 1.00 52.81 AAAA C ATOI 2524 CB SER 263 55.020 34.245 52.885 1.00 46.60 AAA C ATOM 2525 0- SER 263 55.149 33.348 51.791 1.00 66.80 AAAA O ATOll 2527 C SER 263 56.310 35.965 54.117 1.00 49.52 PAA C ATOll 2528 SER 263 57.396 35.737 54.709 1.00 42.33 AAAA 0 ATOl 2529 11 GLU 264 55.320 36.783 54.540 1.00 38.93 AAAA II ATOMl 2531 CA GLU 264 55.362 37.222 55.921 1.00 36.70 AAAA C ATOll 2532 CB GLU 264 54.359 38.337 56.208 1.00 43.71 AAAA C ATOI 2533 CG GLU 264 54.575 39.482 55.213 1.00 37.74 AAAA C ATO 2534 CD GLU 264 55.3741 40.632 55.793 1.00 34.36 AAAA C ATOMl 2535 OE1 GLU 264 55.493 410.600 57.034 1.00 41.55 AAAA O ATOM 2536 OE2 GLU 264 55.832 41.576 55.146 1.00 39.60 AAAA 0 ATOl 2537 C GLU 264 55.098 36.056 56.827 1.00 35.84 AAA C ATOM 2538 O CLU 264 54.368 35.151 56.355 1.00 39.60 AAAA C ATOl 2539 11 GLY 265 55.801 35.938 57.962 1.00 35.64 AAAA i ATOl 2541 CA GLY 265 55.671 34.690 58.727 1.80 40.30 AAAP. C ATO-1 2542 C GLY 265 54.622 34.716 59.829 1.00 39.51 AAAA C ATOH 2543 0 GLY 20G5 53.951 35.699 60.135 1.00 37.20 AAAA 0 ATOII 25-14 II PIlIE 2GG 54.537 33.569 60.516 1.-D 35.75 AAAA I! ATOll 2546 CA PIlE 266 53.-37 33.434 61.625 7.00 33.70 AMAA C ATCHl 2547 CE PHE .6 53.92- 32.155 62.3961.00 28.20 AAAA C ATOl 25-8 CC PHIE 216 53.356 30.958 61.671 1.00 37.07 AAA 7 ATOH 2549 CD1 PHE 266 53.760 30.618 60.377 1.00 34.12 AAAA ATOl 1553 C2 PHE 266 52.383 30.195 62.313 1.00 25.65 AAA C ATOM 2551 CE1 PHE 266 53.225 29.506 59.760 1.00 37.72 AA C ATOl 2552 CE2 PHE 266 51.879 29.094 61.672 1.30 24.63 AAAA C ATOH 2553 C2 PHE 266 52.260 28.708 60.402 .00 23.58 AAA C ATOM 2554 C PHIE 266 53.571 34.570 62.608 1.00 35.82 AAAA C ATOM 2555 O PHIE 266 54.446 35.372 62.979 1.00 39.23 AMA 0 ATOl 2556 11 VAL 267 52.360 3-1.763 63.161 1.00 37.10 AA 2 ATOM 2558 CA VAL 267 52.118 35.812 64.113 1.00 36.09 AAAA C ATOil 2559 CB VAL 267 51.315 36.974 63.567 1.00 39.01 AAAA C ATOll 2560 CGI VAL 267 51.626 37.601 62.230 1.00 31.10 PA"A 7 ATOM 2561 CG2 VAL 267 49.990 36.4100 63.570 1.00 36.88 APA 2 ATOll 2562 C VAL 267 51.506 35.260 65.400 1.00 33.55 AAA C ATOM 2563 O VAL 267 51.202 34.098 65.515 1.00 32.41 AAAP C ATOII 2564 II ILE 268 51.539 36.088 66.4'7 1.00 35.98 AAAA i; ATOM 2566 CA ILE 268 50.867 35.573 67.681 1.00 39.79 AAP C ATOMH .2567 CS ILE 268 51.791 35.232 68.84-9 1.00 31.17 AAAA C ATOl 2 568 CG2 ILE 268 50.922 35.253 70.150 1.00 32.66 AAAA C ATOl 2569 CG1 ILE 268 52.403 33.866 68.724: 1.00 23.56 AAA C ATOl 2570 CD1 ILE 268 53.421 33.546 69.806 1.00 25.93 AAAA C ATOI1 2571 C ILE 268 49.806 36.608 68.060 1.00 42.44 PAPA C ATOII 2572 O ILE 268 50.116 37.767 68.327 1.00 39.99 AAAA O ATOl 2573 i HiS 269 48.528 36.292 67.864 1.00 44.26 PAAA i; ATOI 2575 CA HIS 269 47.491 37.320 68.1,3 1.00 44.28 AAA C ATOll 2576 C IS 269 46.885 37.876 66.901 1.00 45.48 PAAA C ATOl 2577 CG HIS 269 45.915 38.986 67.079 1.DO 54.33 AAAA C ATOII 2578 CD2 HIS 269 44.551 39.014 67.96 1.f-00 46.61 AA ATOIl 2579 1101 IlS 269 46.356 40.2890 67.3, 1.00 51.86 AP ATOl 2591 CE1 llS 269 45.282 41.057 67.437 1.00 55.17 AA ATOl 25E2 ::E2 IlS 269 4-1.175 40.324 671.39 1..1 46.97 AA ATO 2584 C HIS 269 46.423 36.740 69.71 .00 -5.54 -A ATOI 2585 o IIS 69 -16.076 35.55 9.7 1.00 42.94 AA C WO 99/28347 PCT/AU98/00998 ATOI I ATOllI ATOll ATOI I ATO! 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1 FHE 2 PHE 1 PHE 360c 36 1 361 361 361 361 361 361 362 362 3 62 3 62 3C2 362 362 363 363 3C3 363 3-53 364 36-1 364 36-1 364 364 364 364 364 365 365 365 3655 365 366 36 6 366 366 3C6 3(6 3E.7 3G7 367 36(7 367 368 368 368 369 369 369 369 379 37 0 370 370 370 370 3701 371 37 1 37 1 3-71 271 39. 567) 39.4-72 '10.783 410.805 41.943 4I 1 .47 3 42.-297 4 3.61 2 411.834 38.382 3 8. 336G 3 7.5'14 36.372 37 .000 37 .849 38.049 38.628 39. 256 38. 923 35. 295 34. .686 35. 222 34 .402 35.231 35.713 33. 005 32.653 3 2 24 3 30. 954 2 9. 8701 29. 2971 30.485 31 .493 31.870 32 7 T08 32.194 32.992 29. 949 29. 211 2 9.67 8 29.318 28.576 30.158 30. 415 31.885 32.740 34.192 32.118 2 9.97 4 30. 305 2 9.5 2 1 29. 07 2 27 .557 26. 923 26. 697 29.923 29. 965 30.591 31. 487 30. 658 31.300 32.590 32 .35S2 33. 6 31 34 .716 36.073 36.325 3'7. 6G9 36G. 2 0 7 34 64 5 35.569 33. 437 33.089 31. G7 3 3 0.77 1 33.060 33. 228 32. 967 3 3. 2 23 33. 72-I 34 GO'5 33. 371 35.498 S G. 94 2 S4.721 54.782 ,,4.213 54.203 53. 357 974 50. 962 .07 4 49. 719 53. 866 52.661 541. 312 53. 555 52.300 52.610 53.765 5.6716 52.247 53.515 53.113 52. 030 53.875 53.456 53.837 52.558 54 .072 5 5. 0-4 0 ,3 .5771 1;.173 53. 937 54.899 53. 699 54.182 55 02 5.33 53.393 54.2-74 52.819 52.488 51.133 53.473 53.206 54 .517 55. 24 3 55. 241 54 .037 54.373 53.305 56.687 ,7 .2 48 S'7.27 5 58.727 60.073 57 .949 59. 518 60.751 58.818 59. 4C5 59.706 60.298 58.,1'I 7 57.299 5 9. 0)12 53). 121 58.7 36 59. 428 57 .384 58i. 036 57 .700 58. 401' 58. 431 59.052: 58.061 57. 08~ 56. 94: 55. 931 54 .64: 53. 591 S3. 6-2 2.80' S2. 84 3 4/ 58 27.235 25.7141 25. 148 23.266 23. 1160 23.2636 23.631 25.40 24.373 23.885 23.266 22.084 21.411 2-1. 469 20.465 20.408 24 .913 24. 795 26.013 27.139 28. 400 28. 816 27.046 27. 694 2.058 57 17 2 280 241.348 23.338 23.156 21.810 27.427 28.621 29.150 29.768 30. 726 29.762 30. 968 31.350 31.667 32.0,43 32.834 30.896 2 9. 84 9 32 .015' 31. 940 32. 376C 32. 511 31.365 32.845 32. 7 20C 33.75-7 34.742 36. 000 37.091 35. 179 34. 976G 35.831 36.'74 35.784 34 .27 1 34.154 33.619 37.821 38.595 38.285 39. C90 39.816 39. 261 540.412 3 41.596 639. 792 3 40. 356 639. 297 9 38. 01 2 7 37 .76.1 5 37.00-I 2 36. 570 1 .00 1 .00 I 00 1 .00 1 00 1.00 1 .00 1.00 1 .00 1.00 1 .00 1 .00 1 .00 1.00 1 .00 1 coo 1.00 1. 00 1.00 1 .00 1 .00 1.00 1 .00 1.-00 1 .00 1 .00 1 .00 1 .00 1.00 1. 00 1 .00 1 .00 1.00 1.00 1.00 1.00 1 .00 1 .00 1.00C 1 .00 1 .00 1.00 1 00 1.00 1. .0 1 .00 1.00 1.00 1 .00 1. 00 1.00 1 .00 00 I '30 1 .00 1.0.) 1.40 1.00 I Of0, I 00C 1.~0 1 O 1 Ic i DO 1 1 Or I '3 37. .32 3I 1.3-I 11.24 47. 92 50.39 51.36 50. 97 51.-62 54 .112 42.06 38. 93 4 6. 19 -19. 34 40C. 94 42.78 '18. 32 43.59 46.01 49.22 50.32 41.31 4I6.96 52.19 53.73 41.72 53.C6 -18.7,7 51.44 49.83 51.51 44.83 28. 57 38.62 4 1 .4-1 47.53 44 .41 40.28 44 .70 45.28 40.80 42.21 ,13.78 51.52 51.77 51 .17 46.36 48.40 43.66 4.4-1.1 48.80 .11 .69 34 .00 414 .90 4-I .75 48.72 52 .3C.

55.32 64.86B 52.76 48.99 53.86 60.15S 55. 91 -45. 96 *53. 97 I39.77 62 .52 59.33 56. 26 I53.88 5* 5. 50 69. 12 147 .97 4 1.93 I45.48 4 6. 29 4 43. 53 -56. -1S D53. 92 3) 59. SO AXAAA 0 WAA1 AA.AA C AAAA C AAAA C AAAA C WAAA 1 AAAP C WAAAl1 WAAAl1 AAAA C AAAA 0 WAAAl1 AAAA C AAAA C AAAA C AAAA C WAA Ii AAAA C AAA ;I AAAA C AAAA 0 AAAA 11 AAAA C AAA C AAAA 0 AAAA C AAAA 0

WAJAA!

AAAA -C AAAA r- AAAA C AAAA C AAAA C AAA 1; AAAA C AAAA C AAAA 11 WAA 1 AAAA C AAAA C AAAA C AAAA 0 WAAAl1 AAAA C AAAA C AAAA C AAAA C AAAA C AAAA C AAAA 0 kAAA Pi AAAA C AAAA C AAAA C AAAA C

AAAAC

AAAA0 WAA I-1 AAAA C AAAA C AAAA 0 AAAA C XM.A 0 WAAAl1 AAkAA C WAA C- WAA C WAA C AAAA C- WAA C AAAA 0 W1AA :1 WAA C AAAA C WAA 0 WAA C WAA 0 WAAl1 WAA C WAA C AAA C AA.AA C WAA C WAA C WO 99/28347 ATOI I ATOI I ATOI I ATOll ATOI I ATOllI ATOI I

ATOM

ATOI I AT OM ATOMl ATollI ATOllI ATOI I ATOllI

ATOI

ATO! I

ATOI

ATOllI

ATO!

ATOII

ATOM1 ATollI ATOI I AT(Y l ATOllI AT OH ATOil ATOllI ATOllI ATOI I ATol AT Ol ATOll ATOllI ATroi I ATOllI ATOlI

ATOM

ATOM

ATOI I ATOllI

ATOMA

ATollI ATOllI

ATOII

ATOI

ATOI I ATOI I A'rci ATCOI I ATOllI ATOI I

ATOI!

ATOI I ATOI I

ATOI

ATOllI

ATOII

ATOll ATOMl ATOlI ATOMl

ATOM

ATOI I ATOlI ATOil

ATOM

ATOll ATO? I ATollI ATOI I ATO) I ATOI I ATOI I ATOI I ATOllI ATOll ATOI I ATOI I ATOI I ATOI I ATOI I ATOI I ATOi I 352 ?0 3521 3522 3523 3524 3526 352 7 3528 3529 3530 3531 3532 3533 3535 3536 3537 3538 353 9 354 0 354 4 35415 35416 3548 3549 3550 3551 3552 3555 3556 3557 3559 3560 3561 3562 35C3 3564 3565 3566 3568 3569 3570 3571 3572 357 4 3575 3578 3581 3582 3583 3585 3S86 3587 3588 3589 3590 3591 3592 3594 3595 3596 3597 3598 3599 3600 3601 3603 3604 3605 3606 3607 3608 3609 3610 3612 3613 3C14 3615 3617 3618 3619 3C20 3-,2 1 3C2 2 36A2 3 362 4 £02 £110 CT; Pii C £141 O PHE I LEL CA LOUI CB LEU CG LOU CD1 LEU CD2 LELU C LEU 0 LELI III LYS CA LYS CB LYS CG LYS CD LYS CE LYS lIZ LYS C LYS

LYS

I I ASH CA ASH CB ASH CG ASH 001 ASH 11112 ASH c ASH 0 ASH I I LEU CA LOU CO LOU C-3 LEU £01 LEU CD2 LOEl C LELU O LOU H1 ARG CA ARG CB ARG CG ARC CD ARG lIE ARG CZ ARC, 141-i ARG I1112 ARC C ARG

ARC

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LEU

O LEU I I ILE CA ILE CO ILE £02 ILE CCL ILE CDl ILE C ILE

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11 LOUI CA LELU CO LEU CG LEU CDI LOL £02 LOU' C LELU

LOU

IH GLY CA GLY C CLY 0 3LY I I GLLI CA GLU CB CLU CG CLI CID GLU 001 CLUI 002 CIL.' C G LU

GLLU

34 -J-1 35. 119 34. 654 35.005 35.633 36. 928 38. 171 38.411 38.853 39.260 36. 715 37.2M 35. 970 3 5. 5271 34.546 33. 645 32.529 31.674 31.083 365.646 36. 636 37.657 38.765 39.080 38.009 37.892 37.160O 4 0.043 41.031 .10. 0 9 41. 305 41 .099 42.396 43.135 42.030 -11 .71 2 41.151 42.801 43.320 43. 706 44 .288 44 .286 4 5. 377 46. 618 46. 966 47.571 -14 556 4 4.7.-16 4 5. 37?5 46G. 5 26 4 7 .5 96C 48.80( 50.031 4 9. 010 -17.043 46.868 47.448 48.042 47.342 48. 115 4 5.871 44 .999 49.524 49.801 50. 454 51 .866 52.1575 52. 2341 52. 926 52.6C16C 12. c 53. 576 52. 17 5 S2. 931 54.Z49 55. 024: 5I..549 55.849 5G .055 551.4 02 56. 050 56. 1 -30 56.379 5A.07 8 S-71._-I( 35/58 5,1..1 C 35.817 53.716 35.579 54.467 10.895 53.592 41.728 55.305 40.510 55.395 41.109 55.812 40.276, 5.1.800 39.114 55.643 37.934 53.657 39.565 56.392 42.2-13 57.507 42.364 5586 .43.192 56.509 44.415 55.521 45.077 5C.162 46.119 56.955 15.441 57.687 46.460 58.933 45.899 56.863 45.366 57.960 45.907 55.986 15.513 5C.352 46.410 55.154 47.314 54.978 48.396 53.972 49.096 55.965 48.578 56.892 45.786 57.223 46.479 56.893 44.43B 57.371 43.795 57.359 42.288 57.422 11-159 56.112 41.689 57.796 40.041 58. 751 44 .245 59.773 43.877 58.814 44.982 60.155 45-131 60.222 46.928 58.907 47.415 58.817 48.944 57.926 49.410 58.380 49.598 59.64l5 19.383 57.548 50.012 60.544 44.633 C1.728 44.465 59.578 44.219 59.942 43.379 C0.41 1 14 .32 9 59.577 44.667 60.157 43.95-1 59.C96 46.179 59.022 -12.311 57.'788 42.286 59.675 41.199 58.976 40.042 59.303 38.724 58.696 371.574 58.862 38.829 59.S15 37.7165 59.381 40.003 60.595 40.040 58.423 40.067 58.712 40.341 57.531 41.054 57.363 12.554 56.187 13.217 58.625 -13.300 59.01T9 39. 083D 39.788 39.139 58.423 37.972 58.715 3(.702 58.155 36.C62-4 58.657 35.803 57.033 37.272 56.386 37.243 S5.310 38.323 55.7'79 39.63C 55.192 083 53.966 40.890 5..014 41 .7 55.784 35.859 55.52 35.34E 1.00 56.49 1.00 56.39 1.00 54 .84 1.00 52.23 1.00 50.17 1.00 46.25 1.30 44.82 1.00 36.78 1 .00 45.04 1.00 35.55 1.00 42.26 1.00 38.37 1.00 4l7.06G 1.00 50.19 1.00 56. 7 4 1 .00 59.6C4 0.01 60.17 0.01 60.45 0.01 60.38 1.00 49.72 1.00 42. 42 1.00 54 .43 1.00 59.92 1.00 63.16 1.0)0 64.53 1.00 66.40 1.00 52.88 1.00 62.35 1.00 63.08 1.00 58.341 1.00 54.73 1.00 56.41 1.00 54I.12 1.00 37.88 1.00 40.97 1.00 52.37 1.00 52.11 1.00 55.16 1.00 55.45 1.00 58.68 1.00 69.10 1.00 81.17 1.00 84 .46 1.00 85.64 1.00 81.81I 1.00 94.15 1.00 50.16 1.00 44.25 1.00 50.99 1.00 49.40 1.00O 64.72 1.00 70.76 1.0)0 63.32 3.00 68.60 1.00 46.33 1.00 45.17 1.00 45.12 1.00 49.10 1.00 46.36 1.00 34.36 1.00 38.59 1.00 37.18 1.00 49.87 1.00 44.72 1.00 49. 97 1.00 48.48 1 .00 48. 44 1.00 50.28 1.00 39.89 1.00 42.89 1.00 50.94 1 .00 54 .23 1 .00 48. 67 1 .00 49. 94 1.00 52 .70 1 .00 49. 94 1 .00 512 .51 1.00 52.33 1.90 45.22 1 .00 512 .91 1 .00 42.11 1.00 40.20 1.00 51 .32 1 .0-0 55.86 1 .00 54 .61 PCT/AU98/00998 AAA-A C AAAA CA AAAA C AAAA 0 AAAA 11 AAAA C AAAA C AAAA C AAAA C AAAA C AAAA C AAAA 0 AAAA 11 AAAA C AAAA C AAAA C A.M.A C AAAA C AAA 1 AAAA C AAAA 0 AAA 1 A.AAA C PAAA C AAAA C AAAA 0 AAAA 11 AAAA C7 n.AAA 0 AAAA C AAAA C AAAA C A.M.A C AAAA 0 AAAA C AAAA £4 AAAA C AAAA C

AAA

AAAA C1 A.M.A CI AAA I1 AAAA C AAAA 0 AAA 11 AAAA C AAAA C ,%AAA C AAAA C AAAA C AAAA C AAAA 0 AAA 11 AAAA C A.MA C

AA.M.

AAAA C AAAA C A.AAA C AAAA 0 A.M.A 11 AAAA C- AAAA C AAAA C AAAA C A.AAA C A.M.A C A.AAA 0 WAAAl1 AAAA C AAA C- AAAA 0 AAA 11 AAAA C AAAA C AAAA C AADAA C AAAA 0 ?AAAA AP.AA C AAAA 0 WO 99/28347 PCT/AU98/00998 3 6/5 8 ATM 1 3 G2 5 11 1 382 5.1.980 1_5. 19 3_5 57 00 5 3. 5 G AAAk 1 ATOM 3627 CA GLLO 382 5b. 091 55. C18 3 3. 76 G 1 .00 48.1IS AAAA C ATOM4 3628 CR GLIA) 382 55.051 53.550 3 3. 53 2 1 00 35.27 AAAA C AT01 1 3629 CG GI 3FI2 54 .739 53.225 32. 051 1.00 4 9. 69 AAAA C AT01 l 3630 CD GLU 382 4 .67 6 51.719 31.807 1.00 56.45 AAAA C AT0ll 3631 OE1 GLU 382 55.062 50.924 7 C,5 1.00I 61.66 AAAA 0 AT01l1 3632 OE2 GLU 382 54.261 51.201 30.745 1.00 57.69 AAAA 0 AT01l1 3633 C GLU 382 54 006 55". 732 32. 973 1.00 50.84 AAAA C ATOl 36341 0 GLU 382 53.097 56.282 33. 596 1 .00 19.44 AAAA 0 AT0ll 3635 11 GLII 383 54 .347 56. 256 31.780 1.00 52. 25 AAI I ATOl 3637 CA GUII 383 53.498 57.153 31. 01 C 1.00 40.15 AAAA C AT0ll 3638 CB GLUI 383 53.914I 58.609 31.155 1.00 28. 50 AAkAA C ATOl 3C39 CG GUI 1 383 54.489 58.909 32. 54 2 1.00 31.10 AAA C ATOl 3 6410 CD GUI 1 383 54.950 6i-. 301 32. 752 1.00 33.19 AT'AA C ATOl 364 1 OE1 GUAI 383 55.186 60.8,10 31.6C83 1.00 40.341 AAAA 0 ATOM 364 2 IIE2 GUII 383 55. 04 3 60.9413 33. 934 1.00 36.30 I\AAA I i ATOI4 3645 I: GLM: 383 53.4 2C 56. 74 4 2 9. 563 1 .00) 10. 15 AAAA C AT0ll 36.16 0 GLII 383 541.131 55.858 2P. 139 1.00 4 3. 45 AAAA 0 ATOI i 3C64.7 11 LEU 384 52.375 57. 195 280. 86 0 1.00 42. 54 ANAA I I ATll 364 CA 2t 3. 525 7 56 8 89 27.4,l 13 1.00 4 3. 2.1 ?AAJ.A AT01ll 3650 CB LEU 384I 50.81:1 57.011 26. 94 9 1.00 43.79 M.AA C ATOM 3651 CG LELI 384 49. 818 56.235 271.861 1.-00 41 .21 AAAA C AT01l1 3652 CDI LEU 381 48.611 57. 095 28. 221 1.00 33.99 AAAA C ATOI4 3653 CID2 L17U 364 4 9. 405D 54.968 27 .1,19 1.00 33.20 AAAA C ATOlt 3654 C LEU 384 53.204 57.809 2 6.6G72- 1.00 40.51 AAAA C AT01l1 3655 0 LOU 384 53.582 58 .872 2-7. 177 1.00 29.66 ?A.AA 0 ATOll 3656 11 GL'J 385 53.659 57.319 25.531 1 .00 45. 22 AAAA 11 ATOll1 3658 CA GLLO 385 54 .410 58.116 24.5S70 1.00 49. 98 AN'A C ATOll1 3659 CB G LL 385 54 .424 47 5 23. 174 1.00 60. 5n ?.AAA C ATOll1 3660 CO GLU 3835 55. 04 5 56.095 23 .106 1I. 00 68.76 MxIA. C ATOM 3661 CD GLU 385 54.195 5.1.951 23. 592 1.00 72.0-,7 AAAA C ATOI 1 3662 001 GLLO 385 53. 150 55.213 24.244 1.00 81.88 ?A6AA 0 ATOM1 3663 002 G L 385 54.565 53.786 23.301 1.00 73.13 AAAA 0 ATOMl 3664 C GLL' 385 53.828 59.515 2-1.4 50 1.00 47. 41 AAAA C ATOl1 3665 o GIL' 365 52.635 59.706 24.184 1.00D 54.43 AAkA 0 ATOI4 3666 1-1 CLY 386 54.614 60.470 24. 902 1.00 43.69 AAAA 11 ATOMl 3668 CA GI.± 386 54.181 61.870 24. 897 1.00 40.31 AAAA C ATOM 3669 C GLY 386 54.286 62.449 26.308 1.00 40.65 AAAA C ATOl 3670 0 GLY 386 53.930 63. 615 26. 491 1.00 39. 75 AAAA 0 ATOl 3671 I1 ASII1 3 87 54 .441 61.537 27 .272 1.00 40.75 AAAA 11 ATOH 3673 CA ASH 387 54.479 61. 912 28. 675 1.00 49. 18 AAAA C AT01l1 3674 CB ASH 387 55.500 63. 084 28. 874 1.00 44.41 AAAA C ATOll 3675 Cr. ASHI 387 56.925 62. 541 28.-722 1.00 61.51 AAAA C ATOMl 3676 ODi AS[ I 387 57.199 61.313 28.6C77 1. 00 57.85 AAAA 0 ATOll1 3677 1152 ASII1 387 58.063 63.251 28. 592 1.00 61.96 A.AAA I1 AT0ll 3680 C ASH 307 53.095 62.100 29.299 1.00 48 .46G AAAA C ATOMI 3681 0 ASH1 387 52.836 62. 891 30.218 1.00 48. 99 AAAA 0 ATOl 3682 11 TYR 388 52.2141 61. 116 29.058 1..0-0 46.29 AAAA 11 ATr(ll~ 3684 CA TYR 3818 50. 84C6 61. 199 29. 54 0 1.00 45.09 ?JAA C ATOl1 36595 CB TYR p3F8 -19. 823 C0. 957 28 .JA9 9 1.00 4 0.11U AAP,- C "roll 3686 CO TYR 388 4 9.92 5 -2 056 237.37 3 1 .00 42_4. Nk.A C AT01ll 3,-8-7 CDI TYR 389 50.3-13 C-1.8654 26. 064 1. 00 44.38 A AAA C AT01lI 3688 CEl TlYR .399 5 0. 4Q1 62.8P85 25.1J 57 1. 00 35.51 aAAA C AT01ll 3689 CD2 TY R 388 49.625 f,3. 356 27.709 1.00 44.67 ;*.AAA C ATOMl 3690 CE2 TYTR 388 4 9.6;9)9 64 .428 26.830) 38. 14 AAAA C ATOM 3691 CZ TYR 388 50.087 64.148 25. 555 1.00 41 .27 AAAA C ATOll1 3692 O11 TYR 388 50,151 65.181 24 .604 1.00 50.18 AA 0 ATOl 3694 C TYR 388 50.563 60. 288 30.714 1.00 41.-88 6AAA C ATOl 3695 0 TYR 388 50 727 59.092 30.511 1.00 32. 99 AAAA 0 ATOl1 3696 11 SER 389 50.020 60.917 31.763 1.00 45.42 AAAA I I ATOM 3698 CA SER 389 49.591 60.131 32. 931 1.00 50.13 AAAA C AT01l1 3699 CB SER 389 49.798 60. 894 3.1.261 1.00 45.571 AAAA C AT01 1 3700 00 SER 389 51.185 60.899 34.50.1 1.00 51.-11 AAPA 0 ATOli 3702 C SER 389 48.097 59.813 32.804 1.00 48.11 AAAA C ATOll1 3703 0 FE R 389 47. 68C 58. 792 33. 336 1.00 49 .25S AAAA 0 AT01ll 3704 11 PHlE 390 .17.321 650.685 32. 196 1.00 42.56 AAAzk 11 ATOll1 3706 CA 2118 390 .15.867 60. 595 3 2. 1461 1 .00 40. 76 AAAJ\ C ATOll 3-707 CB PHI. 390 45.241 61.581 33.139 1.00 4 4.80 AAAA C ATOI l 37 08 CG 2110 390 .13.76.) 61.358 33. 328 1.00 40.53 AAAA C ATOM1 3709 CD1 PHE 390 4 3.'4I06 6 0. 2 73 34 .086' 1. 00 40.80 AAA C AToll 3710 CD2 PlE 290 -12.768 62. 157 32.748 1 .00f 35.59 AA.A C AT01ll 3711 CEl PHlE 390 42.0I50 59. 985 34,.312 1. 00 47. 09 AAAA C AT01ll 3712 CE2 PHlE 390 41.4541 61. 824 32 965 1.00 4 4.50 AAAA C ATOMl 3713 CZ PHlE 390 4 1. 063 60.745 33.739 1.00 34 .54 AAAA C ATOll 3714 C PHlE 390I 4 5 .372 60.829 30. 720 1.00 38. 54 AAAA C ATOl1 3715 0 PHlE 390 15.5,12 61. 918 30. 126 1 .00 4 0.269 APA.A 0 AT01ll 3716 11 T';R 391 44 .819 59.818 30. 09C 1.00 3 3.4 .S ;AAA H ATOH 3718 CA TYR 391 4.459C 59.782 28.663 1.00 38.58 AAAA C ATOM 3719 CB TY R 391 45. 579 58. 871 27. 972 1 .00D 38. 95 TAAA C AT0ll 3720 CG TY R 391 45.76C0 59. 006 503 1.00 44 .54 AAJ\ C AT Ill 3-721 CMl 'lY 3 91 .18259.15 26 115 2 1 .00I 47.1i 1 MA C ArOll 37122 CUl T'YE 3-1 4'7 5 .9 993 24. 7 22 1 .00 46. 03 z Caj\'- ATOll1 37 23 C0 D' Y' 36c.1 *I14 .92-7 58. 39. 25 5(31 1. 00 4 6. 9- IPJJ.J C ATOll1 3724 CE2 TYCR 391 .15.157 58. 560 24 212 1.00 47.4E. .AAA C ATOll 3725 CZ TY R 391 4 6.2_?07' 59. 35r, 2'3 .El30 1.300 45. 84 ;!AAA C WO 99/28347 PCT/AU98/00998 AT Oi AT0 Oi AToi ATOll ATOI i ATOI4 ATOMl ATOll AT Oil ATOil AT0ll AT 0ll AT01ll

ATOM

ATOI I ATOI I ATO! 1 ATO! I AT01ll ATOll AT01lI AT01lI

ATOM-

ATOI I

ATOM-

ATOH-

AT Oi ATOMl ATOll ATOiI1 ATOll ATOI I AT01ll AT01ll ATOI I ATOI I ATOI I ATOll ATOll ATOll ATOl

ATOK

AT014

ATOM

ATOM-

ATCI 1I ATOI I AT O.l ATOI I AToll ATOI I AT 01 1 ATOI I ATOll ATOllI ATOll ATOlli ATOll ATOlI ATO1I1

ATOM

ATOI I ATUll AT01ll AT0I I AT01ll AToll1 ATOI I AT01ll AT01 I ATOll ATOI I

ATOM

ATOI l ATOI I

ATOH

ATOll AT0O.l AToll, AT01ll ATloI I AT01 1 ATollI ATOI I ATOI I 3*726 3-728 3729 3*730 3732 3733 3734 3735 3"1 36 3737 3738 3 74 0 3741 3742 3743 3714 37.15 37 16 3717 374 9 3750 3751 3752 3753 3754 3755 3756 3758 37159 3760 3761 3762 3765 37 66 376-7 3)7G9 3770 3-771 3772 3-773 3774 3777 3778 3779 3781 3782 378 3 3784 3785 378 8 3'78 9 37 90 3792 37 93 37941 3795 3796 3797 37 98 3799 3801 3802 3803 3804 3605 3806 3809 3810 3811 3813 3814 3815 3816 3817 3818 3821 392 2 3823 3025 3826 3827 3 8 28 3 e29 3830 3.931

T'YR

T'YR

TYR

VAL.

VAL

VAL

VAL

VAL

VAL

VAL

LELO

LEU

LEU

LEO

LELI

LELI

LEU

LEO

As P

ASP

ASP2

ASP

ASP

ASP

ASP

ASP

ASH

ASI I

ASHT

ASH

ASI I AS1h

ASH

ASH

GLI I GLIl GLI I 13L I '3Lll

GLII

GLI)

GLil GLiI

ASH

ASI I

ASH

ASI

ASI

A LZ II ASI I

I

LEU

LEU

LET.

LEO

LEU

LEO

LEU

LELI

G LlI

GLII

GLII

GLIT

GULII

GLII

GLl

'SLII

GLlI ,3LI1I -31,11 G L;I

'SLIT

G L::

GSLI

GSLII

GSLI;

LEU

LEU

LZU

LEOl IL E

LE:-

LEO

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46. 374 43.1941 .12. 841 412. 41'/ 40. 958 -10. 075 38.61l2 40.666 40. 531 40. 508 4 0. 299 38. 9-18 -11.200 .11 02 3 41.128 42.078 38. 821 38. 760 38.015 36.888 37. 445 36.466 36.7 50 35. 311 35. 936 35. 831 35.299 34. 305 341 .804 35. 992 36. 013 X7. 07 5 32. 932 32. 749 32.073 30. 771 29.848 30. 173 2 9. 817 28. 835 30.628 29. 87 4I 29.-107 29. 717 28. 783 27.969 27 .231 26.S591 2 7 .2518 2 9. 3 67 28. 519c 30. 682 31. 3i2 32.927 3 3. 606 33. 417 35.070 30. 923 31.422 30. 24 1 29.688 28. 236 27. 235 25. 941 25.097 2856 30.490 30.528 31 058 31. 938 31. 215 30. 7 17 30.C7 8 30. 906 30. 3-11 33.113 3 3. 107' 34.073 35.135 36. 37 9 36. -38 37. C-58 36. 919 34 86 34 .258 37/58 5 9. 4 92 _22. 48i1 L58.,232 20. 34 9 58. 103 2e.730 60. 151E 27."'178 59.87,1 2 7.60C,3 (50.880 28.440 650.46,; 28.4"12 61.043 29.841 60.092 26.182 61.277 25.804 59.113 25.383 5r.259 2 3 .9-7 7 59.036 23.096 58.649 21.586 5.879 70.753 57.589 21.244 58. 3 75 2 3. 492 S7.173 23.79 SP.973 212.-1;55 5l8.2115 21 .8T.Ih 5 7.0D73 21 .120 5 6. 47-7 20. 156G 55.573 19.333 56.948 20.180 57.619 23.021 56.385 23.212 E8.495 2.4 58.158 24.776 59.512 26.212 SA3. 394 26. 7 96 58. '109 553 58.816 2 4 .541 59.982 2.4.882 58.055 23.877 58.582 23.421 57.567 22.744 57.405 21.257 55.S91 2 0.8e4 0 55.421 21.312 -5411 19.971 59.224 24.458 60.287 241.113 58.681 25.633 5,18 26 .6C32 57.959 27.093 57.430 25.860 58.304 -E.229 1,5. 175 5. .431 59. 945 00 S .9 0 00 0 60rl.558 2 9. 170c 60. 388 2 9. 1,19 (0.283 30.460 58.939 31.13-5 60.608 30.62 61.99" 29.353 C2.909 28.681 62.225 30.4-60G 63.558 30.796 63.331 31.262 63.962 30.316 63.146 30.3-10 63.455 31.191 62.158 29.4-40 641.2S2 31.888 65.477 32.068 C3.389 32.73.1 63.948 33.-756 624.314 35.049 63 .15(l 35.8971 63.430 37.369 C4.502 37.962 0 2 .14 4 3R.222 63.008 34 .052 (61.7183 3 3.9S1.;2 63.580 34.751 62.844 35.331 63.803 35.260O CA..2 3' :23 6 5. 32 33.6-77 63 .6 32960--1 C1.357 -3 61.299 36.692 1 .00; 44 1.O00 39.74 1.00 38.49 1.00 37.07 1.00 39.52 1.-DO 41.12 1.00 37.96 1 .00 33.19 1.00 31.08 1.00 34 .71 1.00 34.62 1 .00 38. 12 1.00 42.498 1 .00 26.48 1.00 2 6. 57 1.00 29 .9 8 1 .00 39.15 1 M 37 .80 1 .00 43.38 1.00 441.77 1.00 44.00 1. 00 17.1-1 1.00 521.91 1.00 4 9. 27 1.00 43.17 1.00 43.51 1 .00 39.90 1.00 4G.32 42. 96 1.00 36. 92 1 21.65 1.00O 27.87 1.00 40. 44 1.00 37 .06 1.00 4 6.7 4 1.00 52.93 1 .00 52. 29 1.00 46.42 1. C0 55.21 1.00 61.17 1 .00r 55.7 9 1 .00 48.64 1.0.0 51.63 1.00 -18. 95 1.00 51.72 1.00 35.94 1.00 4 9.081 1 .0-0 49.32 1.W0 43.31 1.0 53.33 1 52.12 1.00 48.47 1.00 41.81 1.0'0 40.35 1.00 39.03 1 .0C0 52.35 1 .00 49.891 1.00 58.76 1.00 60.1' 3 1.00 59.55 1 .00 73.0)7 1.00 78.39 1.00 71.78 1.0 9.88 1 .00 54 19 1 .00c 51. 96 1.00 50.44 1.00 53.83 1 .00 54 .97 I"1 58. 99 1.0-0 65.82 1 .00 68.10 1. 00 55.35, 1.00 52.09 1.00 511.80 1 0 4 9. 58 1.0)0 49.S7 1.0c0 17. 94 *o46.61 1.0 39.09 .1 C.

51.21 .O 0.

AAAA 02 AAAA 11 NAA C AAAA C2 AAAA C AAAA 02 AAAA 0 AAAA C AAAA C AAAA C2 AAAA C2 AAAA 0 AAAA AAAA 0 AAAA -7

TAAAA(C

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ATOI I ATOI I ATc'i ATODI I 38032 38341 3835 3836 3837 3838 3839 3840 3841 3843 3844 3845 3846 3847 3848 3850 3851 385El2 3853 3854 3855 3856 3857 3859 3860 3861 3862 3863 3864 3865 3866 3868 3869 3870 3871 3872 3873 3875 3876 38 7 7 3878 3879 3880 3881 3882 3884 3885 3886 3887 3888 3890 3993 3 8 9 1 3896 38 97 3900 3903 3904 3905 3907 3908 3909 3910 3911 3914 3915 3 91 C 3918 3*19 3920 3921 3922 3923 3924 3925 3 927 3928 3929 3931 3932 3933 3934 3 93 6 35. 297 34.975 36.2'79 36. 971 37.981 38.286 38.6413 36.719 37.488 39. 212 39.546 39.8920 3 4 .22 3 34.408 33. 503 32.9417 31 .918 30.853 31 .177 29. 693 34 .005 34.245 34 .149 35. 412 35.859 36. 504 37.-294 37 .688 37.7C,3 36.460 37.165 38.477 38.471 38.860 35.034 35.387 34.281 33. 771 32 .352 32.274 33.306 31.130 33.730 34.245 33.239 33. 176r 31. 9413 34 445 34. 470 35.433 3C.5'41 36.165 35. -157 35. 362 3 6. 281 37.56 4 38. 169 38.309 37.880 37. 989 38. 958 40.311 40. 938 41. 986 41.813 43.028 41 257 4 1.251 42 .0411 42.9 42.153 42. 992 43.4-88 0 c4 44.-1 51 44.141 4 5. 28 1 4 6. 588 4 7. 4 54 46C. 87 0 4 8.909, 4 7. 426C 47. 38E2 4 8 .9077 .18. 8917 G63. 14 0 63.090 G62. 953 5897 61 917 60.517 59.467 59.160 c61. 19 9 59. 857 64 .389 65.44 9 64 .418 65. 668 C5. 34 3 66.17 67 .6C25 65 979 66.6C07 6C6.672 67.588 68.588 69.4109 68 .509 67 .34C 66. 813 66.710 68 .622 67 .617 65. 6G2 65.573 C5. 051.

69. 517 70.7109 69.063 69. 861 70.365 71.612 72.285 71 .854 68. 906 69.224 67.709 66. 671 65". 80 5 (5.840 6. B 23 C6.: 073 65. 1510 62. 9510 61 688 60. 66.- 60. 583 61i 4 41 59. 616 C5.74 9 65.081 635. 556 66.240 67 .24 2 C8.429 66 .821 64 .468 03.374 C. 793 63.872 63.250 6. 205 r2. 44, 64 599 65.809 63. 90 3 64 .462 6 4 676 C5. 746 C6,. 103 6 3. 565' 62.35-4 64 .245 63 562 38/58 37 .690 39. 097 39.933 39.737 38.784 39.002 37.7641 ,10.459 40.032 38. 24 9 3 7 .026 37. 263 39.429 38.808 40.551 41 .068 42.151 42. 306 42. 297 42. 4 54~ 41 .607 42. 811 40. 846C 41.291 40.063 39.047 39. 322 38.081 4 0.50C6 37. 694 371. 111 37 982 40.392 39.133 42. 420 42. 504 43.393 44 .496 44 .262 43.409 43.207 ,42. 955 45.693 4C .743 45.460 46.451 46.133 4 459 471.185 45 .577 4 5 400 44 .297 44 .921 44.113 44. .607 4 4 .27 9 43. 469 44 .770 415. 04 8 44 .410 45".4 53 45. 173 46.388 45.947 46G. 24 0 4 25S3 44 .654 4 3. 650 4 2. 9 47 4 1. 7,68 40. 704 4 1. -I9l7 39.486 42. 485 42.370 42 .424 4 2. 131 43.385 44 .157 .13. 162 4 1.218 41 317 4 288 39. 291 1.00 54.58 1 .00 59.76 1.00 59. 56 1.00 58. 17 1.00 53.18 1.00 56.61 1.00 43.25 1.00 53.50 1.00 57,.66 1.00 51. 44 1.00 53.69 1.00 50.75S 1.00 64.09 1.00 61.98 1.00 68.85 1.00 67.83 1.00 72. 19 1.00 73. 08 1.00 71 .67 1.00 75.08 1.00 66.63 1.00 67. 18 1.00 69.29 1.00 77.11 1.00 79.10 1.00 82.59 1.00 84 .82 1.00 84.56 1.00 80. 95 1.90 83. 37 1.00 80.33 1.00 85.91 1.00 86.36 1.00 85.05 1. 00 81.60 1.00 84. 57 1.00 84 .45 1.00 87.48 1.00 88.04 1.00 92.54 1 .00 94 .82 1.00 95.26 1.00 87.80 1.00 92.18 1 .00 84. 46 1 .00 82. 87 1.00 76. 32 1.00 85.77 1.00 89.38 1.00) 83.74 1.01) 79. 60 1. 030 77 .84 7 .00r 81.91 1. 00 86. 97 100 86. 94 1 .00 92. 14 1.00 97.06 1.00 96.33 1.00 76.72 1.00 77.47 1.00 75.75 1.03 73.79 1.00 74.46 1.00 82.51 1.00 90.33 1 .00 84 .46 1.00 65. 97 1.00 63.82 100 61.41 100 60.90 ±00 62. 98 1.0 5 7 7 1 .00 54.06 1.00 55.74 1.00 61.19 1.00 60.64 1.00 63.74 1.00 60.44 1.00O 67.08 1.00 74 .29 1. 00 48. 56 1.00 56.62 10 5.99 1 .00I 53. 97 1 .00 53. 2 9 AAAA 11 AAAA C AAAA C AAAA C AAAA C AAAA C AAN(. C AAAA CI AAAA 11 AAAA C

AAAAC

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IIA

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1.00 40. 91 1.00 56.20 1.00 35.91 1 .00 40.40 1.00 34.81 1 .00 38.49 3.00 39.50 1.00 32.02 1.00 39-148 1.00 39.29 1.00 34 .56 1.00 36.81 1.00 38.80 1.00 44 .20 1.00 58.10 1.00 44 .18 1.00 42.19 1.00 '15.84 1.00 45.87 1.00 .17.19 1.00 43.44 1.00 38.43 1 .00 5,1. 21 1 .00 46.44 1.00 4 6. 63 1.00 44 .68 1 .00 44 .64 1.00 47.69 1.00 43.06 1.00 39.21 1.00 30.88 1 .00 41 .77 1.00 36.08 1 .00 410. 41 1.00 '40.03 1 .00 '15.5.1 1 54. 18 .1 .00 4 9.23 1 .00 47.65 1.00 4 .(r 51.1i0 1.00 144.0C1 1 .00 41 65 1 .00 38.35 1.00 45.35 1 .00 46.86 1.00 43.60 1.00 47.9,-.

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4 14 1 -14 3 I I PRO

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VAL

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15. 4 1: 36. 135 34.832 34.~47 1 34.277 34 .067 35. 011 32.792 34 .7 55 3 3.736C 35.849 35. 982 37. 377 38.287 39.413 39. 985 41. 252 35".7 79 3 5. 879 35.530 35.193 31 .256 32.7-79 32 405 32 .433 3 6. -12 1 3 6. 46C5 37 .345 3e. 507 38.4 9'1 37. 76C9 3 9. 8?7C 39.888 39 .623 39.158 -10.9011 'Ii .898 41.969 43. 190 4 3. 2 94 4 3. 510 44.246 ,15.624 46.547 46. 221 47.370 -18. 315 47 .480 4C. 27 2 4 6. 768 9S5 46.129 4 5. 303' 4IS. 64 5 416. 3 9-" 45'. 76G8 .17 .637 45.7 35 4 6.-I 21 44 .748 4 4.4 46C -12. 947 42.047 -12. 114 4 1. 15-1 44. 9671 45. 933 6S) 46.722if S. 746G 4 4.324 16C. C72 4 8 C, 1 7 48. 860 4 8. 30C 4 9. 4 97 '19. 734 51.191 52. 082 51. 459 40. 3507 4 9 91 4 S SI1C' 37. 23 4 45/58 17.619 C 7,5. 301 ill.561 75. 16C- 14 915' '7C.492 24.22-I 7'7.627 15.220 79.003 14.626 '19.7771 14.381 79.328 14.398 73.947 1-.005 73.508 13.456 73.188 13.908 71.990 13.089 71.930 12?.480 '73.128 12.494 72.968 11.471 741.310 11.027 74.136, 10.262 710.701 13.872 '70. 74.1 15.092 69.585 13.199 68.356 13.896 67.529 13.039 67.860 12.875 69.15-1 13.595 C7.707 11.395 67.509 14.229 66.709 15.165 6'7.54 3 13.2C62 G-.8 22- 13.367 65. 39.7 12. 7 65.319 11.5241 6-1 .766 12.756, G3.291 12.404 67.645 12.608 C68.568 11.942 67.499 12. 887 68.335 12.2039 69.753 121.747 70.035 13.376 67.711 12.240 66.601 12.740 68.389 11.604 67.874 11.509 68.683 10.5,98 70.162 10.568 71.0.45 10.983 '70. 4 04 11.4.72 72.289 10.897 G7.773 12.896 66.747 13.32G 68.738 13.732 68.73C 15.169 69.887 15-729 '7.232 17.159 '71.5-45 17.1-7 72.610 17. 327,- /1.4 52 17.0265 67.-136 15.841 67.018 16.761 66.C61 11-47-I C5.347 15.932 6,1.977 15.699 66 .008 16.267 66.563 17.387 66.399 15.492 G4.211 15.238 63. 04 2 11.C34 64.513 1-1.163 63.42- 13.528 63.677 12.024 62.788 11.226 -33.243 11.514 62.9671 9.7I66 C3.3551 14.210 62.5602 13.838 64.318 15.063 G4.424 15.855 C5.910 6.8 66. 105 16.5 89S C5.342 16.178 v7128 171. 4CC 63. 617 713 62 .18-I 37 264 (-1.012 1 0:1 -7.808 6 5. 46A5 1.70O 93.79 07.01 89?. 69 I 9 87.19 0.01 92.',4 1.00 99. 93 1.00103.59 1.00103.27 1. 00108.0OC' 1.00 85.31 1 .00 83. 41 1.00 82. 1.00 73.49 1 .00 73.13 1.C 76I. 33 1 .00 80.62 01 76. 66 0.01 76. 20 1.00 67.70 1 .00 69. 99 1 00 61.47 1.00 59.03 1.00 55.20 1 .00 61.941 1.00 44 .78 1 .00 44..63 1.00 59.73 1 .00 57.22 1.00 56.211 iC")j 52.58 1.00 50.27 1.00 11.85 1.00 39.78 1.00 30.43 1.00 53.49 1.00 18.33 1.00 50.86 1.00 49.78 1.00 46.06 1.00 83.03 1.00 50.57 1.00 46.55 1.00 52.16 1.00 59.12 1.00 59.71 1.00 76.75, 1.00 80.53 1.00 91.67 1.00 86.00 1.00 56.50 1.60 49.83 1.00 58.37 1.0Q 59. 3C 61.32 1C"7 79.21 1 .72 86.09 1.00 92.00 1.00 96.51 1.00 58.84 1.00 61.93 1.00 516. 57 1.00 551.61 1.00 51.22 1.00 45.27 1.00 56.45 55.11 1.00 58.91 1.00 57.00 1.00 57.39 1 .00 6.1.03 1.00 62.69 1.00 53.71l 1 .0'O 51.88 1.01007.47 1 .00108.287 E8BS C 131328 C2 2888 0 2888 0 8888 C 8828 C 2BB C 8888 C 11888 1I 2888 C 8888 C 2828 C 13888 0 8888 C 8288 C 0888 0 2288 I-I 8888 C 8888 0 8888 C 8288 0 8882 I I 28813 C 2822 C 2222 C 8882 0 8888 0 8880 0 0888 I I 13880 0 8288 0 13828 I I 2888 C 8888 0 8822 0 8888 0 13881 I I 88813 C 8822 0 8888 I I 8888 C 8888 C 8882 0 0826 C, D-000 S WO 99/28347 PCT/AU98/00998 46/58 ATOll 41771 01Q SUL 4 93 38. 152 -791 r. 3 1S 1.-090112.-6,5 DODD 0 ATOl I 17 C SUIL ;93 37.611 8 73 r l.i010 1.00110.21 DODD (1 ATO 1 4.773 03 SUL -193 36.533 555 65. 85C, 1.00109.93 DODD 0 ATOlI 4.1 041 SUL -193 36.333 -8.-978 G3 9 1.00107.58 DODD 0 ATOl 1 .477S S SW. -194 56.567 19.753 66.302 1.00109.81 DODD S ATOll 4776 01 SUlL 1941 L6. 597 19. 128 C-7. 659 1 .00107.90 DODD 0 ATOll1 4777 02 SUlL 4 94 57.964 20.027 65.795 1.00112.59 DODD 0 ATCll 4 7'78 03 SUlL 494 55,749 .006 66.267 1 .00111.35 DODD 0 ATrOl 1 4779 04 SUlL 4941 55.886 18. 792 65.3-79 1.00109.86 DODD 0 ATOI 1 4780 S SVlL 4195 34 .533 11.2410 7 5. 722 1.00114.67 DODD S ATOl I .1i7 81 01 SL'L .195 35. 2741 12.213 76C.5S95 1.00111.38 DODD 0 ATOM .1-f82 02 SUlL 495 35. 47 6 10.329 74 .974 1.00113.60 DODD 0 ATollI 4783 03 SUL .195 33 5 52 11.860 .7 48 1.00112.77 DODD 0 ATOI4 4784 0.1 SL'L 4 95 33.773 10.278 76.6C04 1.00113.18 0000 0 ATOM 4785 S SL'L 496 35.466 24..8.14 519.093 1.00 50.73 DODD S ATOl .14786 01 SUlL 496 35.613 24 .843 6 0. 6 07 1.00 62.519 0000 0 ATollI 4787 02 SUL 4 9C 36.0072 23.581 58. 671 1.00 '48.59 DODD 0 ATOll 1788 03 SUlL -196 35.880 26.084 58.1155 1.00 56.7.1 DODD 0 ATOll J- 78 9 04 SLUL 496 33. 958 2.953 59. 034 1.00 59.34 DODD 0 ATOMI 4790 S SLIL 4 9- 47.653 -2.303 70.199 1.00 68.98H DODD S ATOM .1791 01 SUlL -497 .17.849 -1 .058 70096 1 I. 00 68.52 DODD 0 ATOll 4792 02 SUlL 497 18.59-1 509 C9. 072 1.00 70. 94 0000 0 ATOll 47193 03 SL'L .197 416.18-7 3 93 69.810 1.00 73.47 DODD 0 ATOllI .179.1 04 SUlL 4 97 4 7.7 99 -3.446 1.129 1.00 71 .33 DODD 0 ATOllI 4795 S SUlL 498 56. 527 35. 758 7 5. 513 1.00 71 .48 DODD S ATOl .14796 01 SUlL -198 55.870 35.013 7.6 C,2 1 1.00 72. 97 D000 0 ATOll 4797 02 SUlL .l198 57 759 34.99C "--5.1367 1.00 6-9. 11 000000 ATOll1 4798 03 SUlL -199 56. 619 37 .237 75.785 1.0)0 72.45 DODD 0 ATOll 147 99 0. SI!L .196t 55. 623 35.809 -14.230 1.00 7 2. 71 DODD 0 ATOll -1800r IS SIlL 4 99 4 0.63 9 2. 36 6 0. 499 1.-D0 7.1.04 DODD S ATOll1 4801 0 1 SUlL -19 9 -10.2Z'18 ^2C. 03 9 0 45 1 .00 7 6. 00 DODD 0 ATOll .192 02- Sul. -1 99 42. 089 27 .601 69. 835 1.30O 75. 15 DODD 0 ATOll1 4803 03 SUlL .199 39. 823 218.,167 70.098 1.00 '77 .27 DODD 0 ATOll -18c04 04 SUL 4 199 -10.424 17 .2.145 68.018 1 .00 751.70 DODD 0 ATOll 480$ S SUlL 500 14.996 53.228 20.568 1.00 83.89 DODD S ATOll1 4806 01 SUlL 5C0 45. 080 54 .400 21.461 1.00 84.79 DODD 0 ATOll 4807 02 SUlL 500 46.109 52.266 20.827 1.00 90.38 DODD 0 ATOll 4808 03 SUlL 500 45.032 53.674 19.135 1.00 92.23 DODD 0 ATOM 4809 0-1 SUlL 50C)0 43.762 52.396 20.723 1.00 91.61 DODD 0 ATOll .1810 OW NAT 501 2 9. 970 6.90,1 7 7. 7 13 1.00 34 .84 DODD 0 ATOll 48E13 014 NAT 502 42.522 18. 998 78. 232 1.00 55.27 DODD 0 ATOM 41816 014 VAT 5L0 3 37.561 21.003 67.518 1.00 41.63 DODD 0 ATOll 1 .4819 0OW WAT 504 50.446 5. 72 1 63.485 1.00 57.3-7 DODD 0 ATOM~ 1822 OW NAT 505 56. 6G8 2.1.85,1 '72. 729 1.00 57 .34 0000 0 ATOll 1825 ON VA)T 506 50.605 5-7.6C95 22.727 1.00 54.26 0000 0 ATOll 4828 014 VAT 507 55.123 37.781 61 .2 04 1.00 43.71 DODD 0 ATOl1 4831 OW NAT 508 17.4 14 -9.070 '74.793 1.00 48.79 DODD 0 ATOl 4 834 014 NAT 509? -14 .263 20. 885 6-3. 811 1 .00 28.64 DODD 0 ATOll 4 837 OW VIAT 10 45 .0)85S 19.108B 84 .433 1. 00 49.09 DODD 0 ATOll1 4 840 C- NMAT 51 i1 33.1,37 1 -27 115 1.00 60.39 DODD 0 ATOll1 4843 ON MAT 512 19.2179 4.902 254 1.00 55.23 000000 ATOll 4 846 ON 01 AT 5 13 11 .50 -2.93 996 1.,00 57. 51 DODD 0 ATOllI 4949 0O4 NAT 5 14 2 4.59 11 17 .207 56.665 1.00 56.36 DODD 0 ATOll1 4852 OW NAT 515 56. 947 34 .9141 62. 552 1 .00 36.47 000000 ATOll .148 55 014 NAT S1 I 5,18.092 39. 983 66. 234 1.00 30.34 DODD 0 ATOll1 4858 ON I4AT 5 17 48 .30C,8 4 0. 7 26 5C6.768B 1.00 81.69 DODD 0 ATOll 1 -4861 ONI NAT 518 25. 776 2.3515 85.630 1.00 66.34 0000 0 ATOll1 .186.1 ON NIAT 5119 30.64 4 68,108 30.765 1 .00 82.28 DODD 0 ATOl 4867 ON lIAT 52-0 38.739 54 .257 4 3. 611 1.043. 4. 0000 0 ATOl1 4870 OW NIAT 51 22.886 4 .470 C-1.8e71 1.20 48.71 DODD C0 ATOl1 4873 ON NAT 52 30.939 50. 24 9 19.364 1.00 54 .00 1D000 0 ATOllI -187 6 ON MAT 523 32.413 9.0C61 -12 .4.11 1 .00 44.45 000000 ATOll1 4879 OW NIAT 524 11.019 .2.560 55 .6553 1. 00 43. 40 DODD 0 ATOll1 4882 ON) NAT 5125 541.268 51.393 37 .51 3 1.00 55.10 DODD 0 ATOll1 1985 O14 WAl 5216 3-7.130 13.590 'Al.39-7 1.00 .16.4 9 000000 ATol 888 CC- NAT 52-7 42.585 1-'.214 84 472 1 .00I 351.95, 0000 0 ATOl1 .1891 ON NAT 52--8 4 3.6C61 G1 .633 10-150 1.00 41.05 DO00 0) ATOllI 4891 ON NAT 529 27 .980 19.86C2 53.34B 1.00 54.59 D0D0 0 ATOl1 4897 ONI NAT 5.3 0 59.527 38.520 6.1.116 1.00 37.96 DODD 0 ATOl1 4900 ONq NAT 531 2 2. 451 1.0416 57 437 1.00 59.31 DODD 0 ATOlM 4903 ON 1-liT 532 30.380 16.12 3 10. 205 1.00 4 0. 39 0000 0 ATOllI 4906 011 t AT 533 46.8 3, 27 .8 88 CS.85-1I 1.00 52. 3-1 DODD 0 ATOM .1909 ON NAT 534 39. 446 4 9. 001 4 5.37 9 1 .00 416.05 DODD 0 ATOlI 4912 ON NAT 535 46. 992 51 .272 50,.722 1.00 52. 62 000000 ATOll .14915 ON NIAT E36 .14. 26C3 19q. 776C 73. 0172 1.00 4 0.6G1 DODD 0 ATOll 4918 ON1 NAT 5 37 33.6C70 58. 861 20. 848 1.00 51.-56 DODD 0 ATOll -14921 014 NAT 5 38 52.4C9 21.639 73.804I 1.00 61.98 000000 AT01l1 4924 014 WAT 539 49. 985 44 .871 3-7 3 24 1 .00 45.45 DDDD 0 AToll 4927 ON NAT 5-10 24 .074 -1.791 0077 1.00 40.40 DODD 0 ATOll 4930 ON NAT FI4I1 3 5. 207 0.714 79.039 1.00 51. 34 DODD 0 ATOll 1933 01W W-AT 1 31 .231 -1.176 C62.362 1.00 48. 33 DODD 0 ATOll1 4936 014 VIAT E13 4 1 .7 156 55. 2 )0 1.0-0 60. 67 DODD 0 AToll 4039 014L NATr 4 4 48. 564 37.3351 72. G12 71.69 DODD 0 ATOll1 4942 ON NAT 4 5 4 9. 501 40.030 A7 58' 1 .01 44.-8p8 DODD 0 ATOll1 4945 ON NAT 4 6 54.11 7.,9317 G-0.018 1 .00 49. 91 DODD 0 WO 99/28347 PCT/AU98/00998 47/58 30. -1 4 05P3 10, I.0H 84 .1: 310 32. 7 '9 G90.-848 1 5 C 7

ATOI

ATU

EN-D

-18 01 IA LDDD 0 DODD Face I Cleft I Face 2 Face left ace 2Cleft 2 1 ac Face 3 (I32D)lNIOR 25E2613S 262D (61) 32L 8DH (6G) 5P 256L 263S 264E 59R 58FH 28Y (27G) 26E 2551 ,?7Q (8R 91 5L 4Y266F- 27 (2821 (6l 90 5

F

56 A01:53E 242E 241 F (274M) 305E 30' 3 0 2 C) 3 19

M

300K 318Q C (322G) 32 1 Q 347F 31 OT 9K 312D (316S 313S 335R i 115K I E(88V) 83Y 80K 79W (1 40V) 112 58N108R 138Y 272E 240R 270D 298 II0I 336R 314V 344

V)

~43E 338N Wc 2 79S (280G) 346Q FIi.u r e 2 0 00 WO 99/28347 PTA9/09 PCT/AU98/00998 49/58 (a) (b) .00 kDa .04 0 2- 3 150 Elu tio n V olu m e (m I) Figure 3 WO 99/28347 PTA9/09 PCT/AU98/00998 50/58 (a) .4

E

.3C/,

E

.2 0

C)

0.0 0.00 8 0 120 1 60 2 00 E lu tia n V o Iu m e (m 1)

(C)

(b) 12'3 4 2 Figure 4 WO 99/28347 WO 9928347PCT/A U98/00998 51/58 Li 150 Cys rich Loop 255- 265 303 313 L2 Figure WO 99/28347 PCT/AU98/00998 2/58 IGFIR LI1 IR L ILLY P EGFR LI 1 L E EGFR L2 311 IR L2 310 IGFiR L2 300 v IIG r I L LI S KA E DY RS 42 V IIE G al L L MF KT R pE0F A D 48 VVfLGNLEI TYVORN Y D 51 S I SG6D L I PVAFR(7)PP LD P 0 367 V I INGS I I NI RGGN NL AA E LE 355 ISG IE NK RRGN NI A S EL E 345 Y R FPPXT VI T YL L FRVAGLESLGDL tpJ~r RGWXL.FY YAL F AMTNL KD GL 100 LSFIKL I D LRYGESKOFNL IR !LP NYA I F LK ELGL106 LIIKIGEV G YVLI AL NT VERI PLENLOI j aG JYYENISYAL vL8 N YD NK GL 106 L 01 LK VK EI T GF LL I AWPENRTDL HAFENL EI R AT Ka 3 QOFSLA SL NI SLGL 426 NLGL E SGYLKERSYALVSLS FFRKLRI R E 7L IN Y 3F Y LDNONL R WO 41a N F AG L G HSHALVSLS F v R E QL I~4P V PJQN Q 1 WD 403 YNLRNI TRO RI ZN PLC LSTVD, S LI D A VS NY V '0 PIKP K G D 150 NLMNITAGS RI EKNNELC LATIO $AS LO SV ED HIVLKDONEEGD 157 K(2)PMRNLEI L HGAVFNALNViQ RV SDLNMSMDF N HL GSCOK 166 RSLKEI SOGOV I SGNKNLC ANTI N KK F 67 SGQKT I S R GENS KA 477 S K HNL TI1 OG KF HYNPKLC 521 HKMEE SGTKGROERND LK T D K ASCEN 470 W DHRNL 7 KA xrAF NP K VSEI YRE GTKGRQSK D ATRN 0 ERA S ES 460

IGFIFI

R

EGFR 02 EGPR 04 150 D L KPMIEKTTINNEYNYR C T N HR C 0 K 157 D I A K K T N PATVINGQFVERCWTH S OK 185 KODP S P N G S M

[;WWGAGEENUCCQKLTKI

480QV H L SP EG W PEPRO V Module I 183 100 189 se Cf IVS rtgr T OCV Ok 615 C T C ~G K AACT E N[N LEjfiT GWF-1A PONOTA V j1HFYA CVrP P I~N 237 IVCTIJCHSGC AC SEC QGCPDDPTKP CRNFyLGICI JC P PIP244 ILS.L.QJ1~JS ORC~RGKSPSE DC NOCA AGCTIGPR ESOL 1 ICK CpLA ~~klF E 1g1r I Trc ~~JQM .JGRG PDC 0 IAH I S 0 IEHI KO OF57 modls~ 2 M0~ie 3 Modi~s 4 r !VEGwaFD1vDRDFVIA NL S A ES S DS EG VI~~~Q75 YY~iFQ WR CV NFSFP IILHHKCKNSRROGCH N ENKCIP28 MLYNPTTYMDVNPEGKYSFG ATICIK K ~P R U? module 5 £IS R-1 6 OSM YmLC P ELE M P 299 El~s M BIT MISSN r LICT PC4P C P A~D 5EMeJE nGVRK KK JEGa JR 310 module a McdueO 7 module a Figure 6 WO 99/28347 WO 9928347PCT/A U98/00998 53/58 Figure 7 WO 99/28347 WO 9928347PCT/AU98/00998 54/58 Figure WO 99/28347 WO 9928347PCT/AU98/00998 55/58 Figure 9: Sequence Alignment of hIGF-1R. hIR and hIRE ectodomains.

Derived by use of the PileUp program in the software package of the Genetics Computer Group, 575 Science Drive, Madison, Wisconsin, USA.

Symbol Comparison table: GenRunData:PileUoPep.Cnp CompCheck: 1254 GapWeight: GapLengthWeight: 0. 1 Name: Name: Name: Higf lr Hi r Hir r Higf lr Hi r Hi rr Higf lr Hi r Hi rr Higflr Hi r Hirr Higf lr Hi r Hirr Higf lr Hi r Hi rr Higf lr Hi r Hirr Higf lr Hi r Hir r Hi gf 1 r Hi r Hirr Hi g fir Hir Hir r Len: 972 CheCk: 1781 Weight: Len: 972 CheCk: 2986 Weight: Len: 972 CheCk: 9819 Weight: 1.00 1.00 1.00

EICGP

HLYPGEVC. P

MNVC.P

RFPKLTVITE

SFPKLIMITD

S FPRLTQVTD

NLKDIGLYNL

HLKELGLYNL

HLRDVALPAL

PPK. ECGDLC DDNEECGDI C LG. EECADVC

GIDIRNDYQQ

GMDI RNNLT.

SLDIRSEVAE

YLLLFRVAGL

YLLLFRVYGL

YLLLFRVYGL

RNITRGAIRI

MNTITRGSVRI

GAVLRGAVRV

PGTMEEKPM.

PGTAKGKTN.

PG VLGAAGE P LKRLENCrVI EGYLNILLIS LHELENCSVI EGHLQILLMF LRQLENCSWV EGHLQILLMF ESLGDLFPNL TVIRGWKLFY ESLKDLFPNL TVIRGSRLFF ESLRDLFPNL A'IIRGTRLFL K. .AEDYRSY

KTRPEDFRDL

TATGED FRGL NYALVI FEMT NYALVI FEMV

GYALVIFEMP

EKNADLCYLS

EKNNELCYLA

EKNQELCHLS

CEKTT INNEY

CPATVINGQF

CkKTTFSGH-T TVDWSLI LDA

TIDWSRILDS

TIDWGLLQPA

VSNNYIVGNK 143 VEDNYIVLNK 149 PGANHIVGNK 145 4

NYRCWTTNRC

VERC"WTHSHC

DYRCWTSSHC

Q;04CPSTCGK 191 QKVCPTICKS 198 QRVCPCPHG. 193

RACI'ENNECC

HGCrAEGLCC MACrARGECC

HPECLGSCSA

HSECLGNCSQ

HTECLGGCSQ

P DNDTACVAC RHYYYAGVCV PDDPTKCVAC RNFYLDGRCV PEDPRACVAC RHLYFQGACL PACPPNTYRF 241 ETCPPPYYHF 248 WACPPGTYQY 243 PSGFIRNGSQ 287 PSGYTMNSSN 298 PSGFTP.NSS. 287 4 4

EGWRCVDRDF

QDWRCVNFSF

ESWRCVTAER

CAN'ILSAES.

CQDLHHKCKN

CSLHSVPG.

4 4 SMYCI ?CEGP LLCrPCLGP SI FCHKCEGL

MNIASELENF

NNLAAELEA

YULE PQLQHS

YSFYVLDNQN

YS FYALDNQN

YTLY-VLDNQN

CPKVCEEEKK

CPKVCHLLEG

CPKECKV. .G MGLI EVVTGY

LGLIEEISGY

LGLVETITGF

LQQLWDWDHR

LRQLWDWSKH

LQQLGSWVAA

SDSEGFV

S RPQGCHQYV

RASTFG

T KTI DSVT SA EKTI DSVTSA

TKTIDSIQAA

VKIRHSHALV

LKIRRSYALV

LKIKHSFALV

NLTIKAGKO4Y

NLTITQGKLF

GLTIPVGKIY

I HDGECMQEC

IHNNKCIPEC

IHQGSCLAQC

QMLQGCrIFK GNLLINIRRG 337 QELRGCrVINGSLIINIRGG 347 QDLVGCrHVE GSLILNLRQG 335

SLSFLKNLRL

SLSFFRKLRL

SLGFFKNLKL

FAFNPKLCVS

FHYNPKLCLS

FAFNPRLCLE

I LGEEQLEGNI i RGETLEIGN I RGDAMVDGN El YRMEEVTG

EIHKMEEVSG

HI YRLEEVTG WO 99/28347 PTA9/09 PCT/AU98/00998 56/58 Hig fir Hir Hi rr Higf lr Hir Hi rr Higfilr Hi r Hir r Hi g fir Hi r Hir r Hig fir Hi r Hi rr Higfir Hi r Hirr Higf 1: Hi r Hir r Higf lr Hi r Hir r Higfilr Hi r Hi r Higfilr Hi r Hir r

TKGRQSKGDI

TKGRQERNDI

TRGRQNKAEI

RDLISFTVYY

RDLLGFMLFY

RDLLS EIVYY

EPGILLHGLK

H PGWLMRGLK

EPGVTLASLK

NTRNNGERAS

ALKTNGDQAS

N PRTNGDRAA KEAP FKNVTE

KEAPYQNVTE

KES PFQNATE

PWTQYAVYVK

PWTQYAI FVK

PWTQYAVFVR

!End of 1-462 fragment CESDV LHFTS TTTSKNRIII TWHRYRPPDY CENEL LKFSY IRTSFDKILL RWEPYWPPD' CQTRT LRFVS NVTEADRILL RWERYEPLEA

YDGQDACGSN

FDGQDACGSN

HVGPDACGTQ

AVTLTMVEND

TL .VTFSDER

AITLTTEEDS

P PsLPNGNLS P PS DPNGNIT P PTQRNGNLT

EVTEN'PKTEV

DSQKHNQSE.

DGDPEAEME.

SWNMVDVDLP

SWTVDI DP P

SWNLLDVELP

HI RGAKS ElL RTYGAKSDI I PHQGAQS PIV

YYIVRWQRQP

HYLVFWERQA

YYLVLWQRLA

PNKDV

LRSNDPKSQN

L..SRTQ

YI RTNASVPS

YVQTDATNPS

YLRTLPAAPT

QDGYLYRHNY

EDSELFELDY

EDGDLYLNDY

532 547 530 582 596 580

IPLDVLSASNSSSQLIVKWN

VPLDPISVSNSSSQIILKWK

VPQDVISTSNSSSHLLVRWK

4 CSKD. KIPIR CLKGLKLPS R

CHRGLRLPTS

KQAEKEEAEY

ILKELEESSF

P PLEAQEAS F AA. TYNIT

AAFPNTSSTS

GPLRLGGNSS

MHEAEKLGCS

NQDTPEERCS

NHAAHTVGCS

NPNGLI LMYE

EPNGLIVLYE

DPNIGLI LKYE

QATSLSGNGS

RATS LAGNGS RAT SLAGNGS

KYADGTIDIE

TWS. PPFESE N. NDPRFDGE RKVFEN FLHN RKT FEDYLHN

QKKFENFLHN

DPEELETEYP

VPTSPEEHRP

DFEIQEDKVP

ASN FVFARTM

VAAYVSARTM

AAT FVFARTM IKYGS .QVED

VSYRRYGDEE

IKYRRLGEE-A

WTDPVFFYVQ

WTEPTYFYVT

WTDSVAFYIL

CGGEKGPCA

YEDSAGECCS

SDCCP

C PKTEAE

PKTDSQ

CQHPPPGQVL

SIFVPRPERK RRDVMQVANTTMSSRSRNTT WVFVPRPSRK RRSLGDVGNVTVAVP .TV AITIPISPWK VTSINKSPQR D.SGRHRRAA FFES RVDNKE F. EKVVNkKE

.RE

PAEGADDI PG P EAXADDIVG

PHREADGIPG

QRECVSRQEY

LHLCVS RKH F TVLCVS RLRY AKTGYEN FlH DYLDVP SNIA GP EEEDAGGL

RTVISNLRPF

SLVISGLR-IF

RAVLS GLR.HF P VT WEP RPEN PVTHEI FENN KVAWEAS S N

RKYGGAKLNR

ALERGCRLRG

AKFGGVHLAL

TLYRIDIHSC 776 TGYRIELQAC 786 TEYRIDIHAC 764 SIFLKWPEPE 826 VVHLMWQEPK 836 SVLLRWLEPP 814 LNPGNYTARI 875 LSPGNYSVRI 886 LPPGNYSARV 864 WO 99/28347 PTA9/09 PCT/AU98/00998 57/58 21 Fab 0 0 C1 o 1 2 3 4 5 6 7 8 9 10 1112 13 1415 16 17 181920 Elution Volume (ml) Figure WO 99/28347 WO 9928347PCT/AU98/00998 58/58 Schematic interpretations of EM images Projection along: Sape y axis z axis x axis hIR

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83-7/83-14 Figure 11 23. A computer-assisted method according to claim 21 or claim 22, which further includes the step of selecting one or more chemical structures from step which interact with the receptor site of the molecule in a manner which prevents the binding of natural ligands to the receptor site.

24. A computer-assisted method according to any one of claims 21 to 23, which further includes the step of obtaining a compound with a chemical structure selected in steps and and testing the compound for the ability to decrease an activity mediated by the receptor.

A computer-assisted method according to claim 21, in which the method is used to identify potential compounds which have the ability to increase an activity mediated by the receptor molecule.

26. A computer-assisted method according to claim 25, further including the step of obtaining a molecule with a chemical structure selected in steps and and testing the compound for the ability to increase an activity mediated by the receptor.

27. A computer-assisted method according to any one of claims 21 to 26, in which the molecule of the insulin receptor family is the IGF-1R.

28. A computer-assisted method according to any one of claims 21 to 26, in which the molecule of the insulin receptor family is the insulin receptor.

0' 29. A method of screening of a putative compound having the ability to 0 modulate the activity of a receptor of the insulin receptor family, including the "000." steps of identifying a putative compound by a method according to any one of claims 1 to 28, and testing the compound for the ability to increase or decrease an activity mediated by the receptor.

A method according to claim 29, in which the test is carried out in vitro.

31. A method according to claim 29, in which the test is a high throughput 32. A method according to claim 29, in which the test is carried out in vivo.

33. A method according to claim 29, in which the test is carried out in vivo.

34. A method according to claim 1 substantially as hereinbefore described with reference to any one of the Examples or Figures.

Dated this thirteenth day of May 2002 Commonwealth Scientific and Industrial Research Organisation Patent Attorneys for the Applicant: F B RICE CO

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e e

Claims (19)

1. A method of designing a compound able to bind to a molecule of the insulin receptor family and to modulate an activity mediated by the molecule, including the step of assessing the stereochemical complementarity between the compound and the receptor site of the molecule, wherein the receptor site includes: amino acids 1 to 462 of the receptor for IGF-1, having the atomic coordinates substantially as shown in Figure 1; a subset of said amino acids, or; amino acids present in the amino acid sequence of a member of the insulin receptor family, which form an equivalent three-dimensional structure to that of the receptor molecule as depicted in Figure 1.

2. A method according to claim 1, in which the compound is selected or modified from a known compound identified from a database.

3. A method according to claim 1, in which the compound is designed so as to complement the structure of the receptor molecule as depicted in Figure 1.

4. A method according to any one of claims 1 to 3, in which the compound has structural regions able to make close contact with amino acid residues at the surface of the receptor site lining the groove, as depicted in Figure 2.

5. A method according to any one of claims 1 to 4, in which the compound has a stereochemistry such that it can interact with both the L1 and L2 domains of the receptor site.

6. A method according to any one of claims 1 to 4, in which the compound has a stereochemistry such that it can interact with the L1 domain of a first monomer of the receptor homodimer, and with the L2 domain of the other monomer of the receptor homodimer.

7. A method according to any one of claims 1 to 4, in which the interaction of the compound with the receptor site alters the position of at least one of the WO 99/28347 PCT/AU98/00998 48 L1, L2 or cysteine-rich domains of the receptor molecule relative to the position of at least one of the other of said domains.

8. A method according to claim 7, in which the compound interacts with the p sheet of the L1 domain of the receptor molecule, thereby causing an alteration in the position of the L1 domain relative to the position of the cysteine-rich domain or of the L2 domain.

9. A method according to claim 7, in which the compound interacts with the receptor site in the region of the interface between the L1 domain an the cysteine-rich domain of the receptor molecule, thereby causing the L1 domain and the cysteine-rich domain to move away from each other. A method according to claim 7, in which the compound interacts with the hinge region between the L2 domain and the cysteine-rich domain of the receptor molecule, thereby causing an alteration in the positions of the L2 domain and the cysteine-rich domain relative to each other.

11. A method according to any one of claims 1 to 10, in which the stereochemical complementarity between the compound and the receptor site is such that the compound has a Ki, for the receptor side of less than

12. A method according to claim 11, in which the Ki, is less than

13. A method according to any one of claims 1 to 12, in which the compound has the ability to increase an activity mediated by the receptor molecule.

14. A method according to any one of claims 1 to 12, in which the compound has the ability to decrease an activity mediated by the receptor molecule. A method according to claim 14, in which the stereochemical interaction between the compound and the receptor site is adapted to prevent the binding of a natural ligand of the receptor molecule to the receptor site. WO 99/28347 PCT/AU98/00998 49

16. A method according to claim 14 or claim 15, in which the compound has a K 1 of less than

17. A method according to claim 16, in which the compound has a K, of less than 10' 0 M.

18. A method according to claim 17, in which the compound has a K, of less than

19. A method according to any one of claims 1 to 18, in which the receptor is the IGF-1R. A method according to any one of claims 1 to 18, in which the receptor is the insulin receptor.

21. A computer-assisted method for identifying potential compounds able to bind to a molecule of the insulin receptor family and to modulate an activity mediated by the molecule, using a programmed computer including a processor, an input device, and an output device, including the steps of: inputting into the programmed computer, through the input device, data comprising the atomic coordinates of the IGF-1R molecule as shown in Figure 1, or a subset thereof; generating, using computer methods, a set of atomic coordinates of a structure that possesses stereochemical complementarity to the atomic coordinates of the IGF-1R site as shown in Figure 1, or a subset thereof, thereby generating a criteria data set; comparing, using the processor, the criteria data set to a computer database of chemical structures; selecting from the database, using computer methods, chemical structures which are structurally similar to a portion of said criteria data set; and outputting, to the output device, the selected chemical structures which are similar to a portion of the criteria data set.

22. A computer-assisted method according to claim 21, in which the method is used to identify potential compounds which have the ability to decrease an activity mediated by the receptor.