An ensemble view of thrombin allostery.
Biol Chem
; 393(9): 889-98, 2012 Sep.
Article
in En
| MEDLINE
| ID: mdl-22944689
ABSTRACT
Thrombin is the central protease of the coagulation cascade. Its activity is tightly regulated to ensure rapid blood clotting while preventing uncontrolled thrombosis. Thrombin interacts with multiple substrates and cofactors and is critically involved in both pro- and anticoagulant pathways of the coagulation network. Its allosteric regulation, especially by the monovalent cation Na(+), has been the focus of research for more than 30 years. It is believed that thrombin can adopt an anticoagulant ('slow') conformation and, after Na(+) binding, a structurally distinct procoagulant ('fast') state. In the past few years, however, the general view of allostery has evolved from one of rigid structural changes towards thermodynamic ensembles of conformational states. With this background, the view of the allosteric regulation of thrombin has also changed. The static view of the two-state model has been dismissed in favor of a more dynamic view of thrombin allostery. Herein, we review recent data that demonstrate that apo-thrombin is zymogen-like and exists as an ensemble of conformations. Furthermore, we describe how ligand binding to thrombin allosterically stabilizes conformations on the continuum from zymogen to protease.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thrombin
Language:
En
Journal:
Biol Chem
Journal subject:
BIOQUIMICA
Year:
2012
Type:
Article
Affiliation country:
United kingdom