Author(s): Esmon CT
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Abstract Despite its rather recent identification, the protein C activation system has afforded many investigators with unique opportunities to probe the molecular basis by which cofactors function. Thrombomodulin clearly exerts its specificity switch both by interacting directly with the fibrinogen binding site on thrombin (exosite 1) and by altering the conformation within the enzyme center. At least in the case of thrombomodulin, these conformational changes appear to overcome repulsive interactions between acidic residues in the substrate and the enzyme. To determine whether the models derived from attempts at the molecular analysis of the protein C activation complex are at all relevant to the other coagulation complexes will require further examination, but the concept that residues near the cleavage site contact residues in the free enzyme in an unfavorable fashion, and that the cofactors overcome these inhibitory interactions is a hypothesis that is directly testable for all of the complexes. The availability of crystal structures for the coagulation enzymes, coupled with the capacity to mutagenize both the substrate and the enzyme, promises to provide new insights into molecular events that control coagulation.
This article was published in Thromb Haemost
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