HUMAN THROMBIN BINDING AND RECOGNITION SITES

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Thrombin is a key enzyme in blood coagulation; its significance to health problems (e.g. circulatory diseases and stroke) cannot be underestimated. The studies proposed here contribute to a more detailed description of thrombin action at the molecular level as a basis for future pharmacological therapy. The long term goals of this research are to understand the structure and function of human thrombins at the molecular level. The specific aims of this project are to 1) formulate a detailed map of the thrombin active site and its immediate periphery including the measurement in solution of interatomic distances; 2) Describe and characterize the fibrinogen recognition site by characterizing and identifying these Alpha-thrombin regions or residues involved in fibrinogen binding, and how they differ in the non-coagulant Gamma-thrombin form. 3) Examine these specific binding regions as platelet receptor agonists in thrombin induced platelet aggregation secretion phenomena. 4) Examine other thrombin-macromolecule interactions at the molecular level (hirudin, Alpha2-macroglobulin). These studies will involve the combined biochemical disciplines of enzymology, fluorescence, ESR, NMR and laser photo CIDNP NMR. Alpha-Thrombin plays a central bioregulatory role in hemostasis besides its primary function of catalyzing the conversion of fibrinogen to a clot. One cannot undervalue its importance in the medical sciences when recognizing that deaths and disabilities exceed those caused by cancer or any other health disorder. It is clear that the understanding and eventual control of thrombin function in hemostasis is a high priority in medical research.