Journal
ACS CHEMICAL BIOLOGY
Volume 7, Issue 5, Pages 811-816Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb2004516
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Funding
- Medical Research Council
- Wellcome Trust
- MRC [G0901526] Funding Source: UKRI
- Medical Research Council [G0901526] Funding Source: researchfish
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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 alpha C-helix. By comparison with a previously published structure of CDK9/cyclin T/human immunodeficiency virus TAT we find that the CDK9 alpha C-helix has a degree of conformational variability that has the potential to be exploited for inhibitor design.
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