Glycoprotein Ibα inhibitor complex structure reveals a combined steric and allosteric mechanism of von Willebrand factor antagonism

Platelet glycoprotein Ib alpha (GpIb alpha) interactions with von Willebrand factor (VWF) are a critical early event in platelet adhesion, which contributes to hemostasis and thrombosis. Here we report the structure of a complex between GpIb alpha and a potent peptide inhibitor. The cyclic peptide (CTERMALHNLC) was isolated from a cysteine-constrained phage display library, and in the complex this forms one and a half turns of an amphipathic alpha-helix, the curvature of which facilitates contacts with the curved concave face of the GpIb alpha leucine-rich repeats. The peptide has only limited overlap with the VWF binding site. It effectively inhibits by stabilizing an alternative alpha-helical conformation of a regulatory loop that forms an extended beta-hairpin upon VWF binding. The structure defines a previously unrecognized binding site within GpIb alpha and represents a clear strategy for developing antiplatelet agents targeting the GpIb alpha-VWF interaction allosterically. (Blood. 2009; 114:4883-4885)