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

Abstract

Platelet glycoprotein Ibα (GpIbα) 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 GpIbα 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 α-helix, the curvature of which facilitates contacts with the curved concave face of the GpIbα leucine-rich repeats. The peptide has only limited overlap with the VWF binding site. It effectively inhibits by stabilizing an alternative α-helical conformation of a regulatory loop that forms an extended β-hairpin upon VWF binding. The structure defines a previously unrecognized binding site within GpIbα and represents a clear strategy for developing antiplatelet agents targeting the GpIbα-VWF interaction allosterically. © 2009 by The American Society of Hematology.