title: Glycoprotein Ibalpha inhibitor complex structure reveals a combined steric and allosteric mechanism of von Willebrand factor antagonism.
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.
authors.affiliation: Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: McEwan
authors.forename: Robert K
authors.initials: RK
authors.lastname: Andrews
authors.forename: Jonas
authors.initials: J
authors.lastname: Emsley
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D019038:Platelet Glycoprotein GPIb-IX Complex; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; D014841:von Willebrand Factor