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Title: Crystal Structure of Human Cyclin K, A Positive Regulator of Cyclin-Dependent Kinase 9

Abstract

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 displaymore » 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.« less

Authors:
; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930291
Report Number(s):
BNL-80995-2008-JA
Journal ID: ISSN 0022-2836; JMOBAK; TRN: US200822%%1451
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Molecular Biology; Journal Volume: 366; Journal Issue: 2
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; 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

Citation Formats

Baek,K., Brown, R., Birrane, G., and Ladias, J. Crystal Structure of Human Cyclin K, A Positive Regulator of Cyclin-Dependent Kinase 9. United States: N. p., 2007. Web. doi:10.1016/j.jmb.2006.11.057.
Baek,K., Brown, R., Birrane, G., & Ladias, J. Crystal Structure of Human Cyclin K, A Positive Regulator of Cyclin-Dependent Kinase 9. United States. doi:10.1016/j.jmb.2006.11.057.
Baek,K., Brown, R., Birrane, G., and Ladias, J. Mon . "Crystal Structure of Human Cyclin K, A Positive Regulator of Cyclin-Dependent Kinase 9". United States. doi:10.1016/j.jmb.2006.11.057.
@article{osti_930291,
title = {Crystal Structure of Human Cyclin K, A Positive Regulator of Cyclin-Dependent Kinase 9},
author = {Baek,K. and Brown, R. and Birrane, G. and Ladias, J.},
abstractNote = {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.},
doi = {10.1016/j.jmb.2006.11.057},
journal = {Journal of Molecular Biology},
number = 2,
volume = 366,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}