Molecular mechanisms of thrombin function |
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Authors: | E Di Cera Q D Dang Y M Ayala |
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Institution: | (1) Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Box 8231, St. Louis (Missouri, 63110 USA), Fax +1 314 362 7183, e-mail: enrico@caesar.wustl.edu, US |
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Abstract: | The discovery of thrombin as a Na+-dependent allosteric enzyme has revealed a novel strategy for regulating protease activity and specificity. The allosteric
nature of this enzyme influences all its physiologically important interactions and rationalizes a large body of structural
and functional information. For the first time, a coherent mechanistic framework is available for understanding how thrombin
interacts with fibrinogen, thrombomodulin and protein C, and how Na+ binding influences the specificity sites of the enzyme. This information can be used for engineering thrombin mutants with
selective specificity towards protein C and for the rational design of potent active site inhibitors. Thrombin also serves
as a paradigm for allosteric proteases. Elucidation of the molecular basis of the Na+-dependent allosteric regulation of catalytic activity, based on the residue present at position 225, provides unprecedented
insights into the function and evolution of serine proteases. This mechanism represents one of the simplest and most important
structure-function correlations ever reported for enzymes in general. All vitamin K-dependent proteases and some complement
factors are subject to the Na+-dependent regulation discovered for thrombin. Na+ is therefore a key factor in the activation of zymogens in the coagulation and complement systems. |
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Keywords: | , Allosteric enzymes, blood coagulation, complement, molecular evolution, monovalent cations, protein engineering,,,,,,serine proteases, thrombin, |
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