3 years ago

Reduced state transition barrier of CDK6 from open to closed state induced by Thr177 phosphorylation and its implication in binding modes of inhibitors

Reduced state transition barrier of CDK6 from open to closed state induced by Thr177 phosphorylation and its implication in binding modes of inhibitors
CDK6 is considered as a highly validated anticancer drug target due to its essential role in regulating cell cycle progression at G1 restriction point. Activation of CDK6 requires the phosphorylation of Thr177 on A-loop, but the structural insights of the activation mechanism remain unclear. Methods Herein, all-atoms molecular dynamics (MD) simulations were used to study the effects of Thr177 phosphorylation on the dynamic structure of CDK6-Vcyclin complex. Results MD results indicated that the free energy barrier of the transition from open to closed state decreased ~47.2% after Thr177 phosphorylation. Key steps along the state transition process are obtained from a cluster analysis. Binding preference of ten different inhibitors to open or closed state are also investigated through molecular docking along with MD simulations methods. Conclusions Our results indicated that Thr177 phosphorylation increased the flexibility around the ATP-binding pocket. The transition of the ATP-binding pocket between open and closed states should be considered for understanding the binding of CDK6 inhibitors. General significance This work could deepen the understanding of CDKs activation mechanism, and provide useful information for the discovery of new CDKs inhibitors with high affinity and specificity.

Publisher URL: www.sciencedirect.com/science

DOI: S0304416517303525

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