Format

Send to

Choose Destination
Biophys J. 2001 Dec;81(6):3483-8.

Molecular dynamics simulations of Gly-12-->Val mutant of p21(ras): dynamic inhibition mechanism.

Author information

1
Computational Science Division, Institute of Physical and Chemical Research, Wako-shi, Saitama 351-0198, Japan. foota@gsc.riken.go.jp

Abstract

The mutant p21(ras) protein is a G protein produced by the point-mutated H-ras gene, and this mutant protein has been shown to cause carcinogenesis due to a reduction in its GTPase activity. However, the mechanism underlying this strange phenomenon has still not been elucidated. In our previous study, we have clarified the mechanism of the GTP-->GDP hydrolysis reaction in the wild-type p21(ras) at the atomic level and concluded that GTPase-activating protein plays a significant role in the supply of H2O molecules for the hydrolysis. The structure of the active site in the mutant is the same as that in the wild type. However, by performing molecular dynamic calculations, we found that the structure of the active site of the enzyme substrate complex in the oncogenic mutant p21(ras) continuously changes, and these continuous changes in the active site would make it difficult for the GTP-->GDP hydrolysis reaction to occur in the mutant. These findings can explain the fact that the GTPase activity in the mutant was only 15% of that in the wild type and the fact that GTPase-activating protein has no reaction-activating effect in the mutant. This is a dynamic inhibition mechanism of a vital reaction that can be explained by considering the molecular dynamics.

PMID:
11721009
PMCID:
PMC1301803
DOI:
10.1016/S0006-3495(01)75979-6
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center