A computer modeling study of the interaction between tissue factor pathway inhibitor and blood coagulation factor Xa.
Activation of blood coagulation factor X to factor Xa (FXa) is inhibited by tissue factor pathway inhibitor (TFPI). The second Kunitz-type inhibitory domain (K2) of TFPI binds a catalytic domain of FXa, whereas the first domain (K1) does not. We analyzed computer models of complexes of FXa with K1 or K2, which were made using a crystal structure of FXa. Favorable hydrophobic interaction was observed in the complex of FXa with K2. Furthermore, we constructed a tertiary structure of FXa using CHIMERA to assess the accuracy of a homology modeling method. The isolated model structure of FXa agreed well with the crystal structure, but analyses of complexes of this structure with K1 or K2 revealed that the models of complexes could not provide clear evidence of greater binding ability to K2 because of the positional difference of a few side chains interacting with the inhibitor.
Yoneda
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T
School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Komooka
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Umeyama
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D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D015951:Factor Xa