Structure and function of the platelet receptor Ib receptor. Novel treatments for stroke.

Ischemic stroke is a devastating disease that represents the primary reason for sustained disability and the second leading cause of death worldwide. A better understanding of underlying molecular mechanisms of the disease are required to develop new treatment strategies. The interaction between platelet glycoprotein Iba (GpIbα) and von Willebrand factor (vWF) bound to damaged sub-endothelium represents the first step in platelet adhesion and is essential for normal hemostasis and vascular repair. The interaction is mediated between the N-terminal ligand-binding domain of GpIbα and the vWF-A1 domain and is markedly enhanced as hydrodynamic shear increases, due to conformational activation of vWF or GpIbα or both. In pathological situations, such as stroke or myocardial infarction, vascular damage and enhanced shear rates occurring in stenosised arteries can cause inappropriate activation, GpIbα-vWF binding contributing to thrombus formation. This project involves studying the molecular structure of the three proteins which form the GPIb complex (GPIba,GPIbb,GPIX) in complex with a key co-factor to coagulation enzyme and cell receptor function high molecular weight kininogen. http://www.nottingham.ac.uk/research/groups/structural-biology/index.aspx

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