title: The CDK9 C-helix exhibits conformational plasticity that may explain the selectivity of CAN508.
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 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.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K. sonja.baumli@ncl.ac.uk
authors.forename: Sonja
authors.initials: S
authors.lastname: Baumli
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hole
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
mesh_terms: D001391:Azo Compounds / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000737:chemistry / Q000378:metabolism; D056906:Cyclin T / Q000737:chemistry / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: D001391:Azo Compounds; C568946:CAN 508; D019925:Cyclin A; D056906:Cyclin T; D011720:Pyrazoles; D042863:Cyclin-Dependent Kinase 9