The CDK9 C-helix Exhibits Conformational Plasticity That May Explain the Selectivity of CAN508

• Published in: ACS chemical biology Vol. 7; no. 5; pp. 811 - 816
• Main Authors: Baumli, Sonja, Hole, Alison J, Noble, Martin E. M, Endicott, Jane A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 18.05.2012
• Subjects: Azo Compounds - pharmacology; Binding Sites; Crystallography, X-Ray; Cyclin A - chemistry; Cyclin A - metabolism; Cyclin T - chemistry; Cyclin T - metabolism; Cyclin-Dependent Kinase 9 - antagonists & inhibitors; Cyclin-Dependent Kinase 9 - chemistry; Cyclin-Dependent Kinase 9 - metabolism; Humans; Letters; Models, Molecular; Protein Structure, Secondary; Pyrazoles - pharmacology
• ISSN: 1554-8929; 1554-8937; 1554-8937
• DOI: 10.1021/cb2004516

CDK9 is the kinase of positive transcription elongation factor b and facilitates the transition of paused RNA polymerase II to processive transcription elongation. CDK9 is a validated target for the treatment of cancer, cardiac hypertrophy, and human immunodeficiency virus. Here we analyze different CDK9/cyclin T variants to identify a form of the complex amenable to use in inhibitor design. To demonstrate the utility of this system, we have determined the crystal structures of CDK9/cyclin T and CDK2/cyclin A bound to the CDK9-specific inhibitor CAN508. Comparison of the structures reveals CDK9-specific conformational changes and identifies a CDK9-specific hydrophobic pocket, adjacent to the αC-helix. By comparison with a previously published structure of CDK9/cyclin T/human immunodeficiency virus TAT we find that the CDK9 αC-helix has a degree of conformational variability that has the potential to be exploited for inhibitor design.