Platelet glycoprotein Ibalpha (GpIbalpha) 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
GpIbalpha 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 GpIbalpha
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
GpIbalpha and represents a clear strategy for developing antiplatelet agents
targeting the GpIbalpha-VWF interaction allosterically.
