Chemotherapeutic drug selectivity between wild-type and mutant BRaf kinases in colon cancer
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- 作者：Jianchun Zhang ; Tao Ji
- 关键词：Activation loop ; BRaf kinase ; Chemotherapeutic drug ; Colon cancer ; Phosphorylation
- 刊名：Journal of Molecular Modeling
- 出版年：2017
- 出版时间：January 2017
- 年：2017
- 卷：23
- 期：1
- 全文大小：
- 刊物类别：Chemistry and Materials Science
- 刊物主题：Computer Applications in Chemistry; Molecular Medicine; Computer Appl. in Life Sciences; Characterization and Evaluation of Materials; Theoretical and Computational Chemistry;
- 出版者：Springer Berlin Heidelberg
- ISSN：0948-5023
- 卷排序：23
文摘
Oncogenic BRaf V600E mutation is involved in the development, invasion and metastasis of colon cancer. Selective inhibition of BRafV600E mutant has been recognized as a therapeutic strategy for the cancer. Here, we carried out atomistic molecular dynamics (MD) simulations to characterize the structural basis, energetic property, and dynamics behavior of conformational change in BRaf activation loop upon the mutation. It is found that V600E mutation destabilizes inactive DFG-out conformation of activation loop and promotes its conversion to the active DFG-in conformation, thus conferring constitutive activity for BRaf kinase. A further analysis revealed that the conformational change is induced by electrostatic effect of the negatively charged mutant residue Glu600, which can form a potent salt bridge with the positively charged residue Lys570; this is naturally consistent with phosphorylation of activation loop to activate the kinase. Both of them introduce a negative charge to activation loop and, consequently, the DFG-out is destabilized and conversed to DFG-in. Energetic analysis unraveled that small-molecule kinase inhibitor PLX4720 has a similar selectivity profile for mutant over wild-type kinases and for phosphorylated and dephosphorylated kinases. This can be substantiated in part by in vitro kinase assay that the inhibitor exhibits 12.6 and 10.4-fold higher potencies against mutant than wild type and against phosphorylated than dephosphorylated, respectively. It is suggested that the activation loop conformation, but neither V600E mutation nor phosphorylation, directly determines inhibitor affinity; the mutation and phosphorylation can only indirectly influence inhibitor binding via regulation of activation loop conformation.