Recent Advances in Thrombosis and Hemostasis 2008

pp 80-106

Structural Insights into the Life History of Thrombin

  • James A. HuntingtonAffiliated withDivision of Structural Medicine, Thrombosis Research Unit, Cambridge Institute for Medical Research, Department of Haematology, University of Cambridge

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Thrombin is the ultimate coagulation factor. Not only is it the final protease generated by the blood coagulation cascade, it has more than 12 substrates and 5 cofactors. How thrombin specificity is directed during the four stages of hemostasis is of great interest to the medical community, as insufficient thrombin activity leads to bleeding and excessive activity results in thrombosis. Over the last three decades we have learned a great deal about how thrombin is generated and how it recognizes its several cofactors, substrates, and inhibitors. Although much has been inferred from biochemical studies, our current understanding is primarily based on numerous crystallographic structures of thrombin complexes. In this chapter I provide an overview of the multiple roles thrombin plays in the initiation, amplification, propagation, and attenuation phases of hemostasis, and describe how the special structural features of thrombin are exploited to achieve regulation and substrate selectivity.

Key words

Thrombin Substrate Recognition Crystal structure Exosite