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The structure of CDK8/CycC implicates specificity in the CDK/cyclin family and reveals interaction with a deep pocket binder.
J Mol Biol. 2011 Sep 16; 412(2):251-66.JM

Abstract

Cyclin-dependent kinase (CDK) 8 associates with cyclin C (CycC) and belongs to the CDK module of the Mediator of transcription, together with MED12 and MED13. CDK8 is involved in the regulation of mRNA transcription and was identified as a potent oncogene in colon cancerogenesis. We have solved the 2.2-Å crystal structure of CDK8/CycC in complex with sorafenib, an anti-cancer drug of clinical relevance. The CDK8 structure reveals a unique CycC recognition helix that explains the specificity of the CDK8/CycC pair and discrimination among the highly promiscuous binding in the CDK/cyclin family. In contrast to all CDKs, the CDK8 activation loop appears not to be phosphorylated. Based on the structure, we discuss an alternate mode of CDK8 activation to the general CDK activation by T-loop phosphorylation. Sorafenib binds to the catalytic cleft of CDK8. It displays a deep pocket binding mode and is the first small molecule to induce a DFG-out conformation in the CDK family, which is actually DMG-out in CDK8.

Authors+Show Affiliations

Max-Planck-Institut für Biochemie, Am Klopferspitz 18, D-82152 Martinsried, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21806996

Citation

Schneider, E V., et al. "The Structure of CDK8/CycC Implicates Specificity in the CDK/cyclin Family and Reveals Interaction With a Deep Pocket Binder." Journal of Molecular Biology, vol. 412, no. 2, 2011, pp. 251-66.
Schneider EV, Böttcher J, Blaesse M, et al. The structure of CDK8/CycC implicates specificity in the CDK/cyclin family and reveals interaction with a deep pocket binder. J Mol Biol. 2011;412(2):251-66.
Schneider, E. V., Böttcher, J., Blaesse, M., Neumann, L., Huber, R., & Maskos, K. (2011). The structure of CDK8/CycC implicates specificity in the CDK/cyclin family and reveals interaction with a deep pocket binder. Journal of Molecular Biology, 412(2), 251-66. https://doi.org/10.1016/j.jmb.2011.07.020
Schneider EV, et al. The Structure of CDK8/CycC Implicates Specificity in the CDK/cyclin Family and Reveals Interaction With a Deep Pocket Binder. J Mol Biol. 2011 Sep 16;412(2):251-66. PubMed PMID: 21806996.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The structure of CDK8/CycC implicates specificity in the CDK/cyclin family and reveals interaction with a deep pocket binder. AU - Schneider,E V, AU - Böttcher,J, AU - Blaesse,M, AU - Neumann,L, AU - Huber,R, AU - Maskos,K, Y1 - 2011/07/23/ PY - 2011/05/06/received PY - 2011/07/12/revised PY - 2011/07/13/accepted PY - 2011/8/3/entrez PY - 2011/8/3/pubmed PY - 2011/10/20/medline SP - 251 EP - 66 JF - Journal of molecular biology JO - J Mol Biol VL - 412 IS - 2 N2 - Cyclin-dependent kinase (CDK) 8 associates with cyclin C (CycC) and belongs to the CDK module of the Mediator of transcription, together with MED12 and MED13. CDK8 is involved in the regulation of mRNA transcription and was identified as a potent oncogene in colon cancerogenesis. We have solved the 2.2-Å crystal structure of CDK8/CycC in complex with sorafenib, an anti-cancer drug of clinical relevance. The CDK8 structure reveals a unique CycC recognition helix that explains the specificity of the CDK8/CycC pair and discrimination among the highly promiscuous binding in the CDK/cyclin family. In contrast to all CDKs, the CDK8 activation loop appears not to be phosphorylated. Based on the structure, we discuss an alternate mode of CDK8 activation to the general CDK activation by T-loop phosphorylation. Sorafenib binds to the catalytic cleft of CDK8. It displays a deep pocket binding mode and is the first small molecule to induce a DFG-out conformation in the CDK family, which is actually DMG-out in CDK8. SN - 1089-8638 UR - https://www.unboundmedicine.com/medline/citation/21806996/The_structure_of_CDK8/CycC_implicates_specificity_in_the_CDK/cyclin_family_and_reveals_interaction_with_a_deep_pocket_binder_ DB - PRIME DP - Unbound Medicine ER -