期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 52, 页码 21216-21222出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1218414109
关键词
allostery; thrombosis
资金
- Cell and Molecular Genetics (CMG) training grant (National Institutes of Health) [T32 GM007240]
- Center for Theoretical Biophysics (National Science Foundation) [PHY-0822283]
- National Institutes of Health [HL070999]
- National Science Foundation
- Center for Theoretical Biological Physics (CTBP)
- Howard Hughes Medical Institute
- National Biomedical Computation Resource (NBCR)
- San Diego Supercomputer Center
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1020765] Funding Source: National Science Foundation
The serine protease alpha-thrombin is a dual-action protein that mediates the blood-clotting cascade. Thrombin alone is a procoagulant, cleaving fibrinogen to make the fibrin clot, but the thrombin-thrombomodulin (TM) complex initiates the anticoagulant pathway by cleaving protein C. A TM fragment consisting of only the fifth and sixth EGF-like domains (TM56) is sufficient to bind thrombin, but the presence of the fourth EGF-like domain (TM456) is critical to induce the anticoagulant activity of thrombin. Crystallography of the thrombin-TM456 complex revealed no significant structural changes in thrombin, suggesting that TM4 may only provide a scaffold for optimal alignment of protein C for its cleavage by thrombin. However, a variety of experimental data have suggested that the presence of TM4 may affect the dynamic properties of the active site loops. In the present work, we have used both conventional and accelerated molecular dynamics simulation to study the structural dynamic properties of thrombin, thrombin: TM56, and thrombin: TM456 across a broad range of time scales. Two distinct yet interrelated allosteric pathways are identified that mediate both the pro- and anticoagulant activities of thrombin. One allosteric pathway, which is present in both thrombin: TM56 and thrombin: TM456, directly links the TM5 domain to the thrombin active site. The other allosteric pathway, which is only present on slow time scales in the presence of the TM4 domain, involves an extended network of correlated motions linking the TM4 and TM5 domains and the active site loops of thrombin.
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