A conserved protonation-dependent switch controls drug binding in the Abl kinase

被引：216

作者：

Shan, Yibing ^{[1
]}

Seeliger, Markus A. ^{[2
,3
]}

Eastwood, Michael P. ^{[1
]}

Frank, Filipp ^{[2
,3
]}

Xu, Huafeng ^{[1
]}

Jensen, Morten O. ^{[1
]}

Dror, Ron O. ^{[1
]}

Kuriyan, John ^{[2
,3
]}

Shaw, David E. ^{[1
,4
]}

机构：

[1] DE Shaw Res, New York, NY 10036 USA

[2] Univ Calif Berkeley, Howard Hughes Med Inst, Dept Mol & Cell Biol, Berkeley, CA 94720 USA

[3] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA

[4] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 01期

基金：

美国国家卫生研究院;

关键词：

conformational change; DFG motif; imatinib; molecular dynamics simulation; pH dependence; CRYSTAL-STRUCTURE; PROTEIN-KINASES; CONFORMATIONAL-CHANGES; CATALYTIC SUBUNIT; IMATINIB MESYLATE; FORCE-FIELD; C-ABL; SRC; MECHANISM; INHIBITORS;

D O I：

10.1073/pnas.0811223106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

In many protein kinases, a characteristic conformational change ( the "DFG flip'') connects catalytically active and inactive conformations. Many kinase inhibitors-including the cancer drug imatinib-selectively target a specific DFG conformation, but the function and mechanism of the flip remain unclear. Using long molecular dynamics simulations of the Abl kinase, we visualized the DFG flip in atomic-level detail and formulated an energetic model predicting that protonation of the DFG aspartate controls the flip. Consistent with our model's predictions, we demonstrated experimentally that the kinetics of imatinib binding to Abl kinase have a pH dependence that disappears when the DFG aspartate is mutated. Our model suggests a possible explanation for the high degree of conservation of the DFG motif: that the flip, modulated by electrostatic changes inherent to the catalytic cycle, allows the kinase to access flexible conformations facilitating nucleotide binding and release.

引用

页码：139 / 144

页数：6