Glycoprotein Ibalpha inhibitor complex structure reveals a combined steric and allosteric mechanism of von Willebrand factor antagonism.
P.A.McEwan,
R.K.Andrews,
J.Emsley.
ABSTRACT
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.
Literature references that cite this PDB file's key reference
J.A.López,
and
A.Munday
(2009).
The proof is in the crystal.
Blood,
114,
4757-4758.
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