Ensemble-based modeling and rigidity decomposition of allosteric interaction networks and communication pathways in cyclin-dependent kinases: Differentiating kinase clients of the Hsp90-Cdc37 chaperone

PloS One
Gabrielle StetzGennady Verkhivker

Abstract

The overarching goal of delineating molecular principles underlying differentiation of protein kinase clients and chaperone-based modulation of kinase activity is fundamental to understanding activity of many oncogenic kinases that require chaperoning of Hsp70 and Hsp90 systems to attain a functionally competent active form. Despite structural similarities and common activation mechanisms shared by cyclin-dependent kinase (CDK) proteins, members of this family can exhibit vastly different chaperone preferences. The molecular determinants underlying chaperone dependencies of protein kinases are not fully understood as structurally similar kinases may often elicit distinct regulatory responses to the chaperone. The regulatory divergences observed for members of CDK family are of particular interest as functional diversification among these kinases may be related to variations in chaperone dependencies and can be exploited in drug discovery of personalized therapeutic agents. In this work, we report the results of a computational investigation of several members of CDK family (CDK5, CDK6, CDK9) that represented a broad repertoire of chaperone dependencies-from nonclient CDK5, to weak client CDK6, and strong client CDK9. By using m...Continue Reading

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Citations

Jan 24, 2019·Molecular Pharmacology·John M Streicher
Aug 1, 2020·Frontiers in Molecular Biosciences·Gennady M VerkhivkerPeng Tao
Apr 24, 2020·Journal of Chemical Theory and Computation·Farzaneh JalalypourCanan Atilgan

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Methods Mentioned

BETA
proteomic profiling
PCA

Software Mentioned

YASARA
CNA
CFinder
FIRST
FoldX
YASARA graphics suite
Constraint Network Analysis ( CNA ) interface
MISTIC
CG2AA
iGNM

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