3TNW

Structure of CDK2/cyclin A in complex with CAN508

Summary for 3TNW

• Entry DOI: 10.2210/pdb3tnw/pdb
• Descriptor: Cyclin-dependent kinase 2, Cyclin-A2, 4-[(E)-(3,5-DIAMINO-1H-PYRAZOL-4-YL)DIAZENYL]PHENOL, ... (5 entities in total)
• Functional Keywords: cyclin dependent kinase, kinase cyclin, phosphotransferase, cyclin a, phosphorylation at cdk2 threonine 160, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm, cytoskeleton, centrosome: P24941; Nucleus: P30274
• Total number of polymer chains: 4
• Total formula weight: 128920.88

Authors

Baumli, S.,Hole, A.J.,Endicott, J.A. (deposition date: 2011-09-02, release date: 2012-02-15, Last modification date: 2024-10-09)

Primary citation

Baumli, S.,Hole, A.J.,Noble, M.E.,Endicott, J.A.
The CDK9 C-helix Exhibits Conformational Plasticity That May Explain the Selectivity of CAN508.
Acs Chem.Biol., 7:811-816, 2012

PubMed 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.

PubMed: 22292676
DOI: 10.1021/cb2004516

Experimental method

X-RAY DIFFRACTION (2 Å)