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Differences in the conformational energy landscape of CDK1 and CDK2 suggest a mechanism for achieving selective CDK inhibition

Lookup NU author(s): Daniel Wood, Svitlana Korolchuk, Dr Natalie Tatum, Lan Wang, Professor Jane Endicott, Professor Martin Noble, Dr Mathew Martin

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Dysregulation of the cell cycle characterises many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design.


Publication metadata

Author(s): Wood DJ, Korolchuk S, Tatum NJ, Wang L-Z, Endicott JA, Noble MEM, Martin MP

Publication type: Article

Publication status: Published

Journal: Cell Chemical Biology

Year: 2019

Volume: 26

Issue: 1

Pages: 121-130.e5

Print publication date: 17/01/2019

Online publication date: 21/11/2018

Acceptance date: 11/10/2018

Date deposited: 25/10/2018

ISSN (print): 2451-9456

ISSN (electronic): 2451-9448

Publisher: Cell Press

URL: https://doi.org/10.1016/j.chembiol.2018.10.015

DOI: 10.1016/j.chembiol.2018.10.015


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