Crystal Structure of Human Cyclin K, A Positive Regulator of Cyclin-Dependent Kinase 9
K and the closely related cyclins T1, T2a, and T2b interact with cyclin-dependent kinase 9 (CDK9) forming multiple nuclear complexes, referred to collectively as positive transcription elongation factor b (P-TEFb). Through phosphorylation of the C-terminal domain of the RNA polymerase II largest subunit, distinct P-TEFb species regulate the transcriptional elongation of specific genes that play central roles in human physiology and disease development, including cardiac hypertrophy and human immunodeficiency virus-1 pathogenesis. We have determined the crystal structure of human cyclin K (residues 11-267) at 1.5 {angstrom} resolution, which represents the first atomic structure of a P-TEFb subunit. The cyclin K fold comprises two typical cyclin boxes with two short helices preceding the N-terminal box. A prominent feature of cyclin K is an additional helix (H4a) in the first cyclin box that obstructs the binding pocket for the cell-cycle inhibitor p27{sup Kip1}. Modeling of CDK9 bound to cyclin K provides insights into the structural determinants underlying the formation and regulation of this complex. A homology model of human cyclin T1 generated using the cyclin K structure as a template reveals that the two proteins have similar structures, as expected from their high level of sequence identity. Nevertheless, their CDK9-interacting surfaces display significant structural differences, which could potentially be exploited for the design of cyclin-targeted inhibitors of the CDK9-cyclin K and CDK9-cyclin T1 complexes.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
- Sponsoring Organization:
- Doe - Office Of Science
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 930291
- Report Number(s):
- BNL-80995-2008-JA; JMOBAK; TRN: US200822%%1451
- Journal Information:
- Journal of Molecular Biology, Vol. 366, Issue 2; ISSN 0022-2836
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
CELL CYCLE
COMPLEXES
CRYSTAL STRUCTURE
DESIGN
DISEASES
ELONGATION
GENES
HUMAN POPULATIONS
HYPERTROPHY
LEVELS
PATHOGENESIS
PHOSPHORYLATION
PHOSPHOTRANSFERASES
PHYSIOLOGY
PROTEINS
REGULATIONS
RESIDUES
RESOLUTION
RNA POLYMERASES
SIMULATION
SURFACES
TRANSCRIPTION
national synchrotron light source