Crystal structure of human cyclin K, a positive regulator of cyclin-dependent kinase 9.

Abstract

Cyclin 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 A 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(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.

• Authors: Kyuwon Baek, Raymond S Brown, Gabriel Birrane, John A A Ladias
• Journal: Journal of molecular biology (J Mol Biol) Vol. 366 Issue 2 Pg. 563-73 (Feb 16 2007) ISSN: 0022-2836 [Print] Netherlands
• PMID: 17169370 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CCNK protein, human
• Cyclins
• Multiprotein Complexes
• Transcription Factors
• Cyclin-Dependent Kinase 9

Topics

• Amino Acid Sequence
• Crystallography, X-Ray
• Cyclin-Dependent Kinase 9 (chemistry)
• Cyclins (chemistry)
• Humans
• Models, Molecular
• Molecular Sequence Data
• Multiprotein Complexes (chemistry)
• Protein Folding
• Protein Structure, Secondary
• Protein Structure, Tertiary
• Sequence Homology, Amino Acid
• Structure-Activity Relationship
• Transcription Factors (chemistry)