Thrombin Inhibition by Hirudin: How Hirudin Inhibits Thrombin
作者:
J.W. Fenton II,
G.B. Villanueva,
F.A. Ofosu,
J.M. Maraganore,
期刊:
Pathophysiology of Haemostasis and Thrombosis
(Karger Available online 1991)
卷期:
Volume 21,
issue 1
页码: 27-31
ISSN:1424-8832
年代: 1991
DOI:10.1159/000216259
出版商: S. Karger AG
关键词: Thrombin structure and functions;Hirudin and fragment interactions;Thrombin generation and amplification
数据来源: Karger
摘要:
In addition to its classical active-site regions (catalytic site and adjacent regions), α-thrombin has a unique anion-binding exosite, which is functionally independent of the catalytic site and is involved in fibrin(ogen) recognition. This exosite also accounts for adhesion to negatively charged surfaces (e.g., glass), binding to cell surfaces, and interactions with the anionic tail of hirudin. Hirudin (as an apolar, tridisulfide-linked core structure followed by its anionic tail) interacts with α-thrombin by apolar (e.g., catalytic-site and adjacent regions of thrombin), as well as by ionic binding (e.g., anion-binding exosite). Circular dichroism measurements reveal a sigmoidal nonadditivity for the hirudin tail fragments, which block fibrinogen-clotting activity without interfering with tripeptide chromogenic substrate activities. Such fragments, however, inhibit factor V activation to much lesser extents than hirudin, where factor V activation is the key step in regulating thrombin generation by hirudin or heparin/antithrombin III. Hirudin-derived antithrombotics may thus have differential modes of action in hemostasis and wound healing processe
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