1DX5

Crystal structure of the thrombin-thrombomodulin complex

Summary for 1DX5

• Entry DOI: 10.2210/pdb1dx5/pdb
• Related PRD ID: PRD_000288
• Descriptor: Thrombin light chain, Thrombomodulin, Thrombin heavy chain, ... (9 entities in total)
• Functional Keywords: serine proteinase, egf-like domains, anticoagulant complex, antifibrinolytic complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 194112.57

Authors

Fuentes-Prior, P.,Iwanaga, Y.,Huber, R.,Pagila, R.,Rumennik, G.,Seto, M.,Morser, J.,Light, D.R.,Bode, W. (deposition date: 1999-12-20, release date: 2000-04-10, Last modification date: 2024-11-13)

Primary citation

Fuentes-Prior, P.,Iwanaga, Y.,Huber, R.,Pagila, R.,Rumennik, G.,Seto, M.,Morser, J.,Light, D.R.,Bode, W.
Structural Basis for the Anticoagulant Activity of the Thrombin-Thrombomodulin Complex
Nature, 404:518-, 2000

PubMed 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.

PubMed: 10761923
DOI: 10.1038/35006683

Experimental method

X-RAY DIFFRACTION (2.3 Å)