1e0f
From Proteopedia
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CRYSTAL STRUCTURE OF THE HUMAN ALPHA-THROMBIN-HAEMADIN COMPLEX: AN EXOSITE II-BINDING INHIBITOR
Contents |
Overview
The serine proteinase alpha-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 A crystal structure of the human, alpha-thrombin- haemadin complex. The N-terminal segment of haemadin binds, to the active site of thrombin, forming a parallel beta-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, alpha-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.
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1E0F is a Protein complex structure of sequences from Haemadipsa sylvestris and Homo sapiens. Active as Thrombin, with EC number 3.4.21.5 Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
Crystal structure of the human alpha-thrombin-haemadin complex: an exosite II-binding inhibitor., Richardson JL, Kroger B, Hoeffken W, Sadler JE, Pereira P, Huber R, Bode W, Fuentes-Prior P, EMBO J. 2000 Nov 1;19(21):5650-60. PMID:11060016
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