title: Allosteric inhibition of c-Met kinase in sub-microsecond molecular dynamics simulations induced by its inhibitor, tivantinib.
abstract: 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.
authors.affiliation: School of Pharmacy, Jining Medical University, Rizhao, Shandong 276800, P. R. China. yanmaocai@gmail.com.
authors.forename: Maocai
authors.initials: M
authors.lastname: Yan
authors.forename: Huiyun
authors.initials: H
authors.lastname: Wang
authors.forename: Qibao
authors.initials: Q
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000494:Allosteric Regulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011760:Pyrrolidinones / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*
chemical_list: C551661:ARQ 197; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D011804:Quinolines; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met