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- W2014371855 abstract "The prothrombinase complex, composed of factor Xa and factor Va assembled on a membrane surface, catalyzes the proteolytic formation of thrombin during blood coagulation. The molecular basis for the macromolecular substrate specificity of prothrombinase is poorly understood. By kinetic studies of prethrombin 2 cleavage by prothrombinase in the presence or absence of fragment 1.2, we show that occupation of the active site of the catalyst by inhibitors or alternate peptidyl substrates does not alter the affinity for prethrombin 2. Productive recognition of the macromolecular substrate therefore results from an initial interaction at enzymic sites (exosites) distinct from the active site, which largely determines substrate affinity. This interaction at exosites is evident even in the absence of activation peptide domains responsible for mediating the binding of the substrate to membranes or factor Va. Interactions at the active site with structures surrounding the scissile bond then precede bond cleavage and product release. The second binding step, which appears unfavorable, does not affect substrate affinity but contributes to the maximum catalytic rate. Therefore, binding specificity of prothrombinase for the macromolecular substrate is determined by exosites on the enzyme. We show that competitive inhibition of prethrombin 2 cleavage can be accomplished by interfering with the exosite binding step without obscuring the active site of the enzyme. These findings suggest limitations to the common approach of inferring the basis of factor Xa specificity with active site mutants or the targeting the active site of factor Xa with reversible inhibitors for therapeutic purposes. The achievement of distinctive macromolecular substrate specificities through exosite interactions and modulation of maximum catalytic rate through binding steps may also underlie the reactions catalyzed by the other coagulation complexes containing trypsin-like enzymes." @default.
- W2014371855 created "2016-06-24" @default.
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- W2014371855 date "1997-10-01" @default.
- W2014371855 modified "2023-10-14" @default.
- W2014371855 title "Exosites Determine Macromolecular Substrate Recognition by Prothrombinase" @default.
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- W2014371855 doi "https://doi.org/10.1021/bi970979+" @default.
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