Journal
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
Volume 18, Issue 15, Pages 10367-10374Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5cp07001e
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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.
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