1dx5
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CRYSTAL STRUCTURE OF THE THROMBIN-THROMBOMODULIN COMPLEX
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930], Myocardial infarction, susceptibility to OMIM:[188040], Thrombophilia due to thrombomodulin defect OMIM:[188040]
About this StructureAbout this Structure
1DX5 is a Protein complex structure of sequences from Homo sapiens with , , and as ligands. Active as Thrombin, with EC number 3.4.21.5 Known structural/functional Sites: , , and . Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex., Fuentes-Prior P, Iwanaga Y, Huber R, Pagila R, Rumennik G, Seto M, Morser J, Light DR, Bode W, Nature. 2000 Mar 30;404(6777):518-25. PMID:10761923
Page seeded by OCA on Sun Feb 3 09:35:53 2008