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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Models, Molecular
  • Protein Structure, Secondary
  • Pyrazoles / pharmacology*

Substances

  • Azo Compounds
  • CAN 508
  • Cyclin A
  • Cyclin T
  • Pyrazoles
  • Cyclin-Dependent Kinase 9

Associated data

  • PDB/3TN8
  • PDB/3TNH
  • PDB/3TNI
  • PDB/3TNW