Biochemistry, volume 53, issue 45, pages 7093-7099
Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate
Publication type: Journal Article
Publication date: 2014-11-04
Journal:
Biochemistry
Quartile SCImago
Q1
Quartile WOS
Q3
Impact factor: 2.9
ISSN: 00062960, 15204995
Biochemistry
Abstract
Cancer-associated point mutations in Ras, in particular, at glycine 12 and glycine 13, affect the normal cycle between inactive GDP-bound and active GTP-bound states. In this work, the role of G12V and G13V replacements in the GAP-stimulated intrinsic GTP hydrolysis reaction in Ras is studied using molecular dynamics (MD) simulations with quantum mechanics/molecular mechanics (QM/MM) potentials. A model molecular system was constructed by motifs of the relevant crystal structure (Protein Data Bank entry 1WQ1 ). QM/MM optimization of geometry parameters in the Ras-GAP-GTP complex and QM/MM-MD simulations were performed with a quantum subsystem comprising a large fraction of the enzyme active site. For the system with wild-type Ras, the conformations fluctuated near the structure ready to be involved in the efficient chemical reaction leading to the cleavage of the phosphorus-oxygen bond in GTP upon approach of the properly aligned catalytic water molecule. Dynamics of the system with the G13V mutant is characterized by an enhanced flexibility in the area occupied by the γ-phosphate group of GTP, catalytic water, and the side chains of Arg789 and Gln61, which should somewhat hinder fast chemical steps. Conformational dynamics of the system with the G12V mutant shows considerable displacement of the Gln61 side chain and catalytic water from their favorable arrangement in the active site that may lead to a marked reduction in the reaction rate. The obtained computational results correlate well with the recent kinetic measurements of the Ras-GAP-catalyzed hydrolysis of GTP.
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Khrenova M. G. et al. Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate // Biochemistry. 2014. Vol. 53. No. 45. pp. 7093-7099.
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Khrenova M. G., Mironov V., Grigorenko B., Nemukhin A. Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate // Biochemistry. 2014. Vol. 53. No. 45. pp. 7093-7099.
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TY - JOUR
DO - 10.1021/bi5011333
UR - https://doi.org/10.1021%2Fbi5011333
TI - Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate
T2 - Biochemistry
AU - Khrenova, Maria G.
AU - Mironov, Vladimir
AU - Grigorenko, Bella
AU - Nemukhin, Alexander
PY - 2014
DA - 2014/11/04 00:00:00
PB - American Chemical Society (ACS)
SP - 7093-7099
IS - 45
VL - 53
SN - 0006-2960
SN - 1520-4995
ER -
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@article{2014_Khrenova,
author = {Maria G. Khrenova and Vladimir Mironov and Bella Grigorenko and Alexander Nemukhin},
title = {Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate},
journal = {Biochemistry},
year = {2014},
volume = {53},
publisher = {American Chemical Society (ACS)},
month = {nov},
url = {https://doi.org/10.1021%2Fbi5011333},
number = {45},
pages = {7093--7099},
doi = {10.1021/bi5011333}
}
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MLA
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Khrenova, Maria G., et al. “Modeling the role of G12V and G13V ras mutations in the ras-GAP-catalyzed hydrolysis reaction of guanosine triphosphate.” Biochemistry, vol. 53, no. 45, Nov. 2014, pp. 7093-7099. https://doi.org/10.1021%2Fbi5011333.