6GUH
CDK2 in complex with AZD5438
Summary for 6GUH
| Entry DOI | 10.2210/pdb6guh/pdb |
| Descriptor | Cyclin-dependent kinase 2, 4-(2-methyl-3-propan-2-yl-imidazol-4-yl)-~{N}-(4-methylsulfonylphenyl)pyrimidin-2-amine, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | cdk2, inhibitor, cell cycle |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 35256.94 |
| 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 Cited by 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: 30472117DOI: 10.1016/j.chembiol.2018.10.015 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
Download full validation report
