Structural basis for the anticoagulant activity of the thrombin–thrombomodulin complex

Pablo Fuentes-Prior (), Yoriko Iwanaga, Robert Huber, Rene Pagila, Galina Rumennik, Marian Seto, John Morser, David R. Light and Wolfram Bode ()
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Pablo Fuentes-Prior: Max-Planck-Institut für Biochemie Abteilung Strukturforschung Am Klopferspitz 18a
Yoriko Iwanaga: Max-Planck-Institut für Biochemie Abteilung Strukturforschung Am Klopferspitz 18a
Robert Huber: Max-Planck-Institut für Biochemie Abteilung Strukturforschung Am Klopferspitz 18a
Rene Pagila: Berlex Biosciences
Galina Rumennik: Berlex Biosciences
Marian Seto: Berlex Biosciences
John Morser: Berlex Biosciences
David R. Light: Berlex Biosciences
Wolfram Bode: Max-Planck-Institut für Biochemie Abteilung Strukturforschung Am Klopferspitz 18a

Nature, 2000, vol. 404, issue 6777, 518-525

Abstract: Abstract The serine proteinase α-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 VIII1. Thrombomodulin2, 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 (see, for example, reference 2). Activated protein C then deactivates the coagulation cascade by degrading activated factors V and VIII2. The thrombin–thrombomodulin complex inhibits fibrinolysis by activating the procarboxypeptidase thrombin-activatable fibrinolysis inhibitor3. Here we present the 2.3 Å crystal structure of human α-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.

Date: 2000
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DOI: 10.1038/35006683

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