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

DOI: 10.1021/cb2004516 DOI Help
PMID: 22292676 PMID Help

Authors: Sonja Baumli (University of Oxford) , Alison Hole (University of Oxford) , Martin Noble (University of Oxford) , Jane A. Endicott (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: ACS Chemical Biology , VOL 7 (5) , PAGES 811 - 816

State: Published (Approved)
Published: May 2012

Open Access Open Access

Abstract: 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 áC-helix. By comparison with a previously published structure of CDK9/cyclin T/human immunodeficiency virus TAT we find that the CDK9 áC-helix has a degree of conformational variability that has the potential to be exploited for inhibitor design.

Journal Keywords: Binding; Crystallography; X-Ray; Cyclin; Cyclin; Cyclin-Dependent; Humans; Models; Molecular; Protein; Secondary; Pyrazoles

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ESRF ID29