Conformational regulation of the EGFR kinase core by the juxtamembrane and C-terminal tail: A molecular dynamics study

被引:30
作者
Mustafa, Morad [1 ]
Mirza, Amar [1 ]
Kannan, Natarajan [1 ,2 ]
机构
[1] Univ Georgia, Dept Biochem & Mol Biol, Athens, GA 30602 USA
[2] Univ Georgia, Inst Bioinformat, Athens, GA 30602 USA
关键词
active and inactive dimers; allostery phosphorylation; activation loop; G-helix; hinge; ATP; inhibitor design; TMD; ErbB kinase; GROWTH-FACTOR RECEPTOR; PROTEIN-KINASE; CATALYTIC SUBUNIT; ACTIVATION; DOMAIN; MECHANISM; INSIGHTS; ADENOSINE; AFFINITY; COMPLEX;
D O I
10.1002/prot.22862
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The catalytic domain of epidermal growth factor receptor (EGFR) is activated by dimerization, which requires allosteric coupling between distal dimerization and catalytic sites. Although crystal structures of EGFR kinases, solved in various conformational states, have provided important insights into EGFR activation by dimerization, the atomic details of how dimerization signals are dynamically coupled to catalytic regions of the kinase core are not fully understood. In this study, we have performed unrestrained and targeted molecular dynamics simulations on the active and inactive states of EGFR, followed by principal component analysis on the simulated trajectories, to identify correlated motions in the EGFR kinase domain upon dimerization. Our analysis reveals that the conformational changes associated with the catalytic functions of the kinase core are highly correlated with motions in the juxtamembrane (JM) and C-terminal tail, two flexible structural elements that play an active role in EGFR kinase activation and dimerization. In particular, the opening and closing of the ATP binding lobe relative to the substrate binding lobe is highly correlated with motions in the JM and C-terminal tail, suggesting that ATP and substrate binding can be coordinated with dimerization through conformational changes in the JM and C-terminal tail. Our study pinpoints key residues involved in this conformational coupling, and provides new insights into the role of the JM and C-terminal tail segments in EGFR kinase functions. Proteins 2011; 79: 99-114. (C) 2010 Wiley-Liss, Inc.
引用
收藏
页码:99 / 114
页数:16
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