Allosteric inhibition of c-Met kinase in sub-microsecond molecular dynamics simulations induced by its inhibitor, tivantinib

作者：Yan, Maocai^*; Wang, Huiyun; Wang, Qibao; Zhang, Zhen; Zhang, Chunyan

来源：Physical Chemistry Chemical Physics, 2016, 18(15): 10367-10374.

DOI：10.1039/c5cp07001e

• CONFORMATIONAL TRANSITION
• RECEPTOR KINASE
• DFG-FLIP
• CANCER
• PROTEIN
• DISCOVERY
• BINDING
• STATE
• MODE
• ABL

Protein dynamics in the allosteric regulation of enzymes is crucial for understanding the regulation mechanism of enzymes and designing of inhibitors. Kinases have a conserved Asp-Phe-Gly motif (DFG motif) whose conformation determines the activation state of the kinase; however, knowledge on conformational transition of the DFG motif from the active state to the inactive state ("DFG-flip'') is quite limited. Here we report a DFG-flip of c-Met kinase in molecular dynamics (MD) simulations, induced by its allosteric inhibitor tivantinib. Our MD simulations showed that, with the assistance of tivantinib, c-Met may transit from the DFG-in state to the DFG-out state in a sub-microsecond time-scale. A unique binding mode of tivantinib to c-Met was identified to be the key intermediate for the ligand-induced DFG-flip. This study provides a detailed process of inhibitor-induced kinase allostery, as well as important insights into the DFG-flip mechanism and the design of allosteric inhibitors, not only of c-Met, but also of other kinases.

• 出版日期2016-4-21
• 单位济宁医学院