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

DOI: 10.1016/j.chembiol.2018.10.015

Authors: Daniel J. Wood (Newcastle University) , Svitlana Korolchuk (Newcastle University) , Natalie J. Tatum (Newcastle University) , Lan-Zhen Wang (Newcastle University) , Jane A. Endicott (Newcastle University) , Martin E. M. Noble (Newcastle University) , Mathew P. Martin (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Chemical Biology

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 18598 , 13587

Abstract: Dysregulation of the cell cycle characterizes 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.

Journal Keywords: cyclin-dependent kinases; CDK; cell cycle; drug design; X-ray crystallography; activity assay; SPR; ITC; DSF; inhibitor; CDK1; CDK2

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 28/11/2018 10:05

Documents:
1-s2.0-S2451945618303751-main.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)