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CDK1 structures reveal conserved and unique features of the essential cell cycle CDK

DOI: 10.1038/ncomms7769 DOI Help
PMID: 25864384 PMID Help

Authors: Nicholas R. Brown (University of Oxford) , Svitlana Korolchuk (Newcastle University) , Mathew P. Martin (Newcastle University) , Will A. Stanley (Newcastle University) , Rouslan Moukhametzianov (MRC Laboratory of Molecular Biology) , Martin Noble (University of Oxford) , Jane A. Endicott (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 6

State: Published (Approved)
Published: November 2015

Open Access Open Access

Abstract: CDK1 is the only essential cell cycle CDK in human cells and is required for successful completion of M-phase. It is the founding member of the CDK family and is conserved across all eukaryotes. Here we report the crystal structures of complexes of CDK1–Cks1 and CDK1–cyclin B–Cks2. These structures confirm the conserved nature of the inactive monomeric CDK fold and its ability to be remodelled by cyclin binding. Relative to CDK2–cyclin A, CDK1–cyclin B is less thermally stable, has a smaller interfacial surface, is more susceptible to activation segment dephosphorylation and shows differences in the substrate sequence features that determine activity. Both CDK1 and CDK2 are potential cancer targets for which selective compounds are required. We also describe the first structure of CDK1 bound to a potent ATP-competitive inhibitor and identify aspects of CDK1 structure and plasticity that might be exploited to develop CDK1-selective inhibitors.

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography

Other Facilities: ESRF