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ACS Chem Biol. 2012 May 18;7(5):811-6. doi: 10.1021/cb2004516. Epub 2012 Feb 10.

The CDK9 C-helix exhibits conformational plasticity that may explain the selectivity of CAN508.

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Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.


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.

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