期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 26, 页码 10616-10621出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1221953110
关键词
conformational changes; resistance-causing mutations
资金
- Spanish Ministry of Science and Innovation (MICINN) [BIO2010-20166]
- High End Computing Terascale Resource (HECToR) of the Partnership for Advanced Computing in Europe (PRACE) research infrastructure (Tier-1)
- (Tier-0) SuperMUC at the Leibniz-Rechenzentrum (LRZ), Germany (Seventh Framework Programme) [RI-283493]
Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are frequently found in many cancers. It has been suggested that changes in the equilibrium between its active and inactive conformations are linked to its oncogenic potential. Here, we quantify the effects of some of the most common single (L858R and T790M) and double (T790M-L858R) oncogenic mutations on the conformational free-energy landscape of the EGFR kinase domain by using massive molecular dynamics simulations together with parallel tempering, metadynamics, and one of the best force-fields available. Whereas the wild-type EGFR catalytic domain monomer is mostly found in an inactive conformation, our results show a clear shift toward the active conformation for all of the mutants. The L858R mutation stabilizes the active conformation at the expense of the inactive conformation and rigidifies the alpha C-helix. The T790M gatekeeper mutant favors activation by stabilizing a hydrophobic cluster. Finally, T790M with L858R shows a significant positive epistasis effect. This combination not only stabilizes the active conformation, but in nontrivial ways changes the free-energy landscape lowering the transition barriers.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据