Structural biology of factor VIIa/tissue factor initiated coagulation.

Structural biology of factor VIIa/tissue factor initiated coagulation.
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DOI:
10.2741/4066
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发表时间:
2012-06-01
期刊:
Frontiers in bioscience (Landmark edition)
影响因子:
--
通讯作者:
Bajaj SP
Bajaj SP
中科院分区:
其他
文献类型:
--
作者:
Vadivel K;Bajaj SP

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因子VII(FVII)由N-末端γ-羧基谷氨酸结构域、随后的两个表皮生长因子样(EGF 1和EGF 2)结构域和C-末端蛋白酶结构域组成。FVII的活化产生由通过单个二硫键保持在一起的轻链(Gla-EGF 1-EGF 2结构域)和重链(蛋白酶结构域)组成的双链FVIIa分子。在凝血过程中,组织因子(TF,一种跨膜糖蛋白)和FVIIa的复合物激活因子IX(FIX)和因子X(FX)。FVIIa在结构上是“酶原样的”,并且当与TF结合时,其更是“活性酶样的”。FIX和FX与FVII具有结构同源性。三个结构生物学方面的FVIIa/TF在此审查。一,可溶性TF(sTF)中与FVIIa相互作用的区域以及FVIIa中Ca 2+、Mg 2+、Na+和Zn 2+位点的定位及其功能;二,模拟FXa和FIXa的Gla和EGF 1结构域与FVIIa/sTF的相互作用区域;三,FVIIa/sTF中不完全形成的氧阴离子空穴及其由底物/抑制剂诱导。最后,对TF通路抑制剂的识别元件进行了综述。
Factor VII (FVII) consists of an N-terminal gamma-carboxyglutamic acid domain followed by two epidermal growth factor-like (EGF1 and EGF2) domains and the C-terminal protease domain. Activation of FVII results in a two-chain FVIIa molecule consisting of a light chain (Gla-EGF1-EGF2 domains) and a heavy chain (protease domain) held together by a single disulfide bond. During coagulation, the complex of tissue factor (TF, a transmembrane glycoprotein) and FVIIa activates factor IX (FIX) and factor X (FX). FVIIa is structurally “zymogen-like” and when bound to TF, it is more “active enzyme-like.” FIX and FX share structural homology with FVII. Three structural biology aspects of FVIIa/TF are presented in this review. One, regions in soluble TF (sTF) that interact with FVIIa as well as mapping of Ca2+, Mg2+, Na+ and Zn2+ sites in FVIIa and their functions; two, modeled interactive regions of Gla and EGF1 domains of FXa and FIXa with FVIIa/sTF; and three, incompletely formed oxyanion hole in FVIIa/sTF and its induction by substrate/inhibitor. Finally, an overview of the recognition elements in TF pathway inhibitor is provided.
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