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Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex | | P Fuentes-Prior
; Y Iwanaga
; R Huber
; R Pagila
; G Rumennik
; M Seto
; J Morser
; D R Light
; W Bode
; | | Date: |
30 Mar 2000 | | Journal: | Nature, 404 (6777), 518-25 | | Abstract: | The serine proteinase alpha-thrombin causes blood clotting through proteolytic cleavage of fibrinogen and protease-activated receptors and amplifies its own generation by activating the essential clotting factors V and VIII. Thrombomodulin, a transmembrane thrombin receptor with six contiguous epidermal growth factor-like domains (TME1-6), profoundly alters the substrate specificity of thrombin from pro- to anticoagulant by activating protein C. Activated protein C then deactivates the coagulation cascade by degrading activated factors V and VIII. The thrombin-thrombomodulin complex inhibits fibrinolysis by activating the procarboxypeptidase thrombin-activatable fibrinolysis inhibitor. Here we present the 2.3 A crystal structure of human alpha-thrombin bound to the smallest thrombomodulin fragment required for full protein-C co-factor activity, TME456. The Y-shaped thrombomodulin fragment binds to thrombin’s anion-binding exosite-I, preventing binding of procoagulant substrates. Thrombomodulin binding does not seem to induce marked allosteric structural rearrangements at the thrombin active site. Rather, docking of a protein C model to thrombin-TME456 indicates that TME45 may bind substrates in such a manner that their zymogen-activation cleavage sites are presented optimally to the unaltered thrombin active site. | | Source: | PubMed, pmid10761923 doi: 10.1038/35006683 | | Services: | Forum | Review | Favorites | |
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