6GUB

CDK2/CyclinA in complex with Flavopiridol

Summary for 6GUB

• Entry DOI: 10.2210/pdb6gub/pdb
• Descriptor: Cyclin-dependent kinase 2, Cyclin-A2, 2-(2-chlorophenyl)-8-[(3~{R},4~{R})-1-methyl-3-oxidanyl-piperidin-4-yl]-5,7-bis(oxidanyl)chromen-4-one, ... (4 entities in total)
• Functional Keywords: cdk2, cyclina, inhibitor, cell cycle
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 131148.17

Authors

Wood, D.J.,Korolchuk, S.,Tatum, N.J.,Wang, L.Z.,Endicott, J.A.,Noble, M.E.M.,Martin, M.P. (deposition date: 2018-06-19, release date: 2018-12-05, Last modification date: 2024-01-17)

Primary citation

Wood, D.J.,Korolchuk, S.,Tatum, N.J.,Wang, L.Z.,Endicott, J.A.,Noble, M.E.M.,Martin, M.P.
Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition.
Cell Chem Biol, 26:121-130.e5, 2019

PubMed 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.

PubMed: 30472117
DOI: 10.1016/j.chembiol.2018.10.015

Experimental method

X-RAY DIFFRACTION (2.52 Å)