Structural analysis of the KGD sequence loop of barbourin, an alpha(IIb)beta(3)-specific disintegrin

Disintegrins constitute a class of small proteins that inhibit platelet agg regation by binding to the fibrinogen receptor, also referred to as integri n alpha(IIb)beta(3). Contrarily to other disintegrins that bind to a series of integrins via their Arg-Gly-Asp domain, the recognition site of barbour in contains a Lys-Gly-Asp sequence that ensures its specificity towards alp ha(IIb)beta(3). In this article, a three-dimensional model of barbourin is proposed using homology modeling and large-scale molecular dynamics simulat ions. The conformations of the Lys-Gly-Asp sequence of barbourin are analyz ed and compared to those of peptidomimetics that exhibit similar specificit y towards alpha(IIb)beta(3). The tryptophan residue following the Lys-Gly-A sp sequence of the binding domain is shown to play a crucial role in the bi ological activity and the specificity of barbourin. Our results suggest tha t this disintegrin anchors to the binding pocket of the gamma-chain of fibr inogen rather than to those of the Arg-Gly-Asp sequence.