Thrombin is a Na+-activated, allosteric serine protease that plays opposing functional roles in blood coagulation. Binding of Na+ is the major driving force behind the procoagulant, prothrombotic, and signaling functions of the enzyme, but is dispensable for cleavage of the anticoagulant protein C. The anticoagulant function of thrombin is under the allosteric control of the cofactor thrombomodulin. Recent structural advances have shed light on the remarkable molecular plasticity of this enzyme and the molecular underpinnings of thrombin allostery mediated by binding to exosite I and the Na+ site. Thrombin exists in three forms - E∗, E, and E:Na+, which interconvert under the influence of ligand binding to distinct domains. The transition between the Na+-free slow form E and the Na+-bound fast form E:Na+ involves the structure of the enzyme as a whole, and so does the interconversion between the two Na+-free forms E∗and E. E∗is most likely an inactive form of thrombin, unable to interact with Na+ and substrate.
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