［総説］Rational Design to Develop Antithrombotic Drugs from the Relationship between the Structure and Function of $ \alpha $ thrombin

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Many protease inhibitors in the circulating blood inhibit the activity of $ \alpha $-thrombin. Inhibition of $ \alpha $-thrombin by antithrombins is attributable to the characteristics of structural relationships between $ \alpha $-thrombin and antithrombins. The characteristic structures of $ \alpha $-thrombin include loop 60, exosites 1 and 2, hydrophobic pocket, primary specificity pocket, and active site (catalytic triad). Functions of these structures have been clarified by enzyme-substrate reaction and X-ray and NMR-crystallographic analyses. For developing antithrombine drugs that is safely and effectively used for clinical treatment of thrombotic diseases, the precise understandings of relationship between structure and function of α-thrombm are required. Although it has been evidenced that clot-bound thrombm plays more important role in pathophysiological conditions than native (free) thrombin, the structure and function of clot-bound thrombin remains to be clarified. Understanding the structure and function of clot-bound thrombm would provide a potential therapeutic strategy to develop novel antithrombin drugs, which control the activity of the clot-bound thrombin in the circulating blood. In this review paper, first of all we summarized the structure-function relationships based on the studies on native thrombin and mutant thrombin. Secondary, we summarized the mechanism for thrombin receptor activation by $ \alpha $-thrombin and thrombin receptor agonist peptide (TRAP). Finally, we demonstrated our resuits of the studies on the characteristics of clot-bound thrombin

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