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Crystal structure of the human α‐thrombin–haemadin complex: an exosite II‐binding inhibitor
Author(s) -
Richardson John L.,
Kröger Burkhard,
Hoeffken Wolfgang,
Sadler J.Evan,
Pereira Pedro,
Huber Robert,
Bode Wolfram,
FuentesPrior Pablo
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.21.5650
Subject(s) - hirudin , thrombin , thrombomodulin , biology , binding site , biochemistry , discovery and development of direct thrombin inhibitors , plasma protein binding , serine proteinase inhibitors , serine protease , platelet , immunology , enzyme , protease
The serine proteinase α‐thrombin plays a pivotal role in the regulation of blood fluidity, and therefore constitutes a primary target in the treatment of various haemostatic disorders. Haemadin is a slow tight‐ binding thrombin inhibitor from the land‐living leech Haemadipsa sylvestris . Here we present the 3.1 Å crystal structure of the human α‐thrombin– haemadin complex. The N‐terminal segment of haemadin binds to the active site of thrombin, forming a parallel β‐strand with residues Ser214–Gly216 of the proteinase. This mode of binding is similar to that observed in another leech‐derived inhibitor, hirudin. In contrast to hirudin, however, the markedly acidic C‐terminal peptide of haemadin does not bind the fibrinogen‐recognition exosite, but interacts with the heparin‐binding exosite of thrombin. Thus, haemadin binds to thrombin according to a novel mechanism, despite an overall structural similarity with hirudin. Haemadin inhibits both free and thrombomodulin‐bound α‐thrombin, but not intermediate activation forms such as meizothrombin. This specific anticoagulant ability of haemadin makes it an ideal candidate for an antithrombotic agent, as well as a starting point for the design of novel antithrombotics.