4.6 Article

Mechanistic insights into thrombin's switch between slow'' and fast'' forms

Journal

PHYSICAL CHEMISTRY CHEMICAL PHYSICS
Volume 19, Issue 36, Pages 24522-24533

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/c7cp03671j

Keywords

-

Funding

  1. Wake Forest Baptist Comprehensive Cancer Center's NCI Cancer Center Support Grant [P30CA012197]
  2. National Institute of General Medical Sciences [T32-GM095440]
  3. Center for Molecular Signaling at Wake Forest University

Ask authors/readers for more resources

Thrombin is a multifunctional enzyme that plays an important role in blood coagulation, cell growth, and metastasis. Depending upon the binding of sodium ions, thrombin presents significantly different enzymatic activities. In the environment with sodium ions, thrombin is highly active in cleaving the coagulated substrates and this is referred to as the fast'' form; in the environment without sodium ions, thrombin turns catalytically less active and is in the slow'' form. Although many experimental studies over the last two decades have attempted to reveal the structural and kinetic differences between these two forms, it remains vague and disputed how the functional switch between the fast'' and slow'' forms is mediated by Na+ cations. In this work, we employ microsecond-scale all-atom molecular dynamics simulations to investigate the differences in the structural ensembles in sodium-bound/unbound and potassium-bound/unbound thrombin. Our calculations indicate that the regulatory regions, including the 60s, g loops, and exosite I and II, are primarily affected by both the bound and unbound cations. Conformational free energy surfaces, estimated from principal component analysis, further reveal the existence of multiple conformational states. The binding of a cation introduces changes in the distribution of these states. Through comparisons with potassium-binding, the binding of sodium ions appears to shift the population toward conformational states that might be catalytically favorable. Our study of thrombin in the presence of sodium/potassium ions suggests Na+-mediated generalized allostery is the mechanism of thrombin's functional switch between the fast'' and slow'' forms.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available