4EOL
Thr 160 phosphorylated CDK2 H84S, Q85M, K89D - human cyclin A3 complex with the inhibitor RO3306
Summary for 4EOL
| Entry DOI | 10.2210/pdb4eol/pdb |
| Related | 4EOI 4EOJ 4EOK 4EOM 4EON 4EOO 4EOP 4EOQ 4EOR 4EOS |
| Descriptor | Cyclin-dependent kinase 2, Cyclin-A2, (5E)-5-(quinolin-6-ylmethylidene)-2-[(thiophen-2-ylmethyl)amino]-1,3-thiazol-4(5H)-one, ... (6 entities in total) |
| Functional Keywords | protein kinase, cell cycle, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) More |
| Cellular location | Cytoplasm, cytoskeleton, centrosome: P24941 Nucleus: P20248 |
| Total number of polymer chains | 4 |
| Total formula weight | 128469.12 |
| Authors | Echalier, A.,Cot, E.,Camasses, A.,Hodimont, E.,Hoh, F.,Sheinerman, F.,Krasinska, L.,Fisher, D. (deposition date: 2012-04-14, release date: 2013-02-06) |
| Primary citation | Echalier, A.,Cot, E.,Camasses, A.,Hodimont, E.,Hoh, F.,Jay, P.,Sheinerman, F.,Krasinska, L.,Fisher, D. An integrated chemical biology approach provides insight into Cdk2 functional redundancy and inhibitor sensitivity. Chem.Biol., 19:1028-1040, 2012 Cited by PubMed Abstract: Cdk2 promotes DNA replication and is a promising cancer therapeutic target, but its functions appear redundant with Cdk1, an essential Cdk affected by most Cdk2 inhibitors. Here, we present an integrated multidisciplinary approach to address Cdk redundancy. Mathematical modeling of enzymology data predicted conditions allowing selective chemical Cdk2 inhibition. Together with experiments in Xenopus egg extracts, this supports a rate-limiting role for Cdk2 in DNA replication. To confirm this we designed inhibitor-resistant (ir)-Cdk2 mutants using a novel bioinformatics approach. Bypassing inhibition with ir-Cdk2 or with Cdk1 shows that Cdk2 is rate-limiting for replication in this system because Cdk1 is insufficiently active. Additionally, crystal structures and kinetics reveal alternative binding modes of Cdk1-selective and Cdk2-selective inhibitors and mechanisms of Cdk2 inhibitor resistance. Our approach thus provides insight into structure, functions, and biochemistry of a cyclin-dependent kinase. PubMed: 22921070DOI: 10.1016/j.chembiol.2012.06.015 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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