We are interested in obtaining a reliable three dimensional structure for the seven transmembrane domain of thrombine receptor. Thrombin receptor is an integral membrane protein whose interaction with thrombin, a serine protease, at the extracellular region is known to couple with its intracellular interaction with guanine nucleotide-binding regulatory proteins (G proteins); these subsequently trigger cascades of intracellular reactions that activate platelet aggregation, critical for hemostasis and thrombosis, and events in other thrombin-responsive vascular cells. According to survey and analysis by Baldwin (EMBO, 12 1693-1703, 1993), there are about 200 G-protein-coupled receptors which contain the characteristic seven transmembrane helix domains. Among these receptors, three dimensional structures are available for bacteriorhodopsin (with a resolution of 3.5 A in a direction parallel to the membrane plane and lower in the perpendicular direction) and for bovine rhodopsin (with a resolution of 9.5 A horizontal and 47A normal to the membrane plane). Our immediate research plan is to use the three-dimensional structures of bacteriorhodopsin and bovine rhodopsin as a reference to construct a reliable three-dimensional structure for the seven transmembrane helix domain of the thrombin receptor. The methods we will use include extensive model building, energy calculations, and dynamics simulations, which will require access to the graphics systems and computational facilities provided by the Computer Graphics Laboratory.
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