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 ()
Additional contact information
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
References: Add references at CitEc
Citations:
Downloads: (external link)
https://www.nature.com/articles/35006683 Abstract (text/html)
Access to the full text of the articles in this series is restricted.
Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.
Export reference: BibTeX
RIS (EndNote, ProCite, RefMan)
HTML/Text
Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:404:y:2000:i:6777:d:10.1038_35006683
Ordering information: This journal article can be ordered from
https://www.nature.com/
DOI: 10.1038/35006683
Access Statistics for this article
Nature is currently edited by Magdalena Skipper
More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().