title: Structural analysis of the KGD sequence loop of barbourin, an alphaIIbbeta3-specific disintegrin.
abstract: Disintegrins constitute a class of small proteins that inhibit platelet aggregation by binding to the fibrinogen receptor, also referred to as integrin alphaIIbbeta3. 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 alphaIIbbeta3. 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 alphaIIbbeta3. 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 gamma-chain of fibrinogen rather than to those of the Arg-Gly-Asp sequence.
authors.affiliation: UMR CNRS 7565--Structure et Réactivité des Systèmes Moléculaires Complexes, Institut Nancéien de Chimie Moléculaire, Université Henri Poincaré, Vandoeuvrelès-Nancy, France.
authors.forename: H
authors.initials: H
authors.lastname: Minoux
authors.forename: C
authors.initials: C
authors.lastname: Chipot
authors.forename: D
authors.initials: D
authors.lastname: Brown
authors.forename: B
authors.initials: B
authors.lastname: Maigret
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D003435:Crotalid Venoms / Q000737:chemistry* / Q000235:genetics; D019483:Disintegrins / Q000737:chemistry* / Q000235:genetics; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013816:Thermodynamics
chemical_list: D003435:Crotalid Venoms; D019483:Disintegrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C068858:barbourin