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Structural analysis of the KGD sequence loop of barbourin, an αIIbβ3-specific disintegrin

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Abstract

Disintegrins constitute a class of small proteins that inhibit platelet aggregation by binding to the fibrinogen receptor, also referred to as integrin αIIbβ3. Contrarily to other disintegrins that bind to a series of integrins via their Arg-Gly-Asp domain, the recognition site of barbourin contains a Lys-Gly-Asp sequence that ensures its specificity towards αIIbβ3. In this article, a three-dimensional model of barbourin is proposed using homology modeling and large-scale molecular dynamics simulations. The conformations of the Lys-Gly-Asp sequence of barbourin are analyzed and compared to those of peptidomimetics that exhibit similar specificity towards αIIbβ3. The tryptophan residue following the Lys-Gly-Asp sequence of the binding domain is shown to play a crucial role in the biological activity and the specificity of barbourin. Our results suggest that this disintegrin anchors to the binding pocket of the γ-chain of fibrinogen rather than to those of the Arg-Gly-Asp sequence.

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Authors and Affiliations

  1. Laboratoire de Chimie théorique, UMR CNRS 7565 – Structure et Réactivité des Systèmes Moléculaires Complexes, Institut Nancéien de Chimie Moléculaire, Université Henri Poincaré, BP 239, F-54506, Vandoeuvre-lès-Nancy Cedex, France

    Hervé Minoux, Christophe Chipot, David Brown & Bernard Maigret

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  1. Hervé Minoux
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  2. Christophe Chipot
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  3. David Brown
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  4. Bernard Maigret
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Minoux, H., Chipot, C., Brown, D. et al. Structural analysis of the KGD sequence loop of barbourin, an αIIbβ3-specific disintegrin. J Comput Aided Mol Des 14, 317–327 (2000). https://doi.org/10.1023/A:1008182011731

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