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The cryo-electron microscopy structure of the human CDK-activating kinase

View ORCID ProfileBasil J. Greber, Juan M. Perez-Bertoldi, Kif Lim, Anthony T. Iavarone, Daniel B. Toso, Eva Nogales
doi: https://doi.org/10.1101/2020.05.13.094755
Basil J. Greber
aCalifornia Institute for Quantitative Biosciences (QB3), University of California, Berkeley, California 94720, USA
bMolecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
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  • ORCID record for Basil J. Greber
  • For correspondence: ENogales@lbl.gov basilgreber@berkeley.edu
Juan M. Perez-Bertoldi
cBiophysics Graduate Group, University of California, Berkeley, California 94720, USA
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Kif Lim
dDepartment of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA
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Anthony T. Iavarone
eQB3/Chemistry Mass Spectrometry Facility, University of California, Berkeley, California 94720, USA
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Daniel B. Toso
aCalifornia Institute for Quantitative Biosciences (QB3), University of California, Berkeley, California 94720, USA
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Eva Nogales
aCalifornia Institute for Quantitative Biosciences (QB3), University of California, Berkeley, California 94720, USA
bMolecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
dDepartment of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA
fHoward Hughes Medical Institute, University of California, Berkeley, California 94720, USA
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  • For correspondence: ENogales@lbl.gov basilgreber@berkeley.edu
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Abstract

The human CDK-activating kinase (CAK), a complex composed of cyclin dependent kinase (CDK) 7, cyclin H, and MAT1, is a critical regulator of transcription initiation and the cell cycle. It acts by phosphorylating the C-terminal heptapeptide repeat domain of the RNA polymerase II subunit Rpb1, which is an important regulatory event in transcription initiation by Pol II, and it phosphorylates the regulatory T-loop of CDKs that control cell-cycle progression. Here, we have determined the three-dimensional structure of the catalytic module of human CAK, revealing the structural basis of its assembly and providing insight into CDK7 activation in this context. The unique third component of the complex, MAT1, substantially extends the interaction interface between CDK7 and cyclin H, explaining its role as a CAK assembly factor, and it forms interactions with the CDK7 T-loop, which may contribute to enhancing CAK activity. We have also determined the structure of the CAK in complex with the covalently bound inhibitor THZ1 in order to provide insight into the binding of inhibitors at the CDK7 active site and aid in the rational design of therapeutic compounds.

Significance Control of gene expression and the cell cycle is critical for appropriate cell growth and timely cell division. Failure of the mechanisms regulating these processes can result in proliferative diseases. A molecular complex termed the CDK activating kinase (CAK) impinges on both of these regulatory networks in human cells and is thus a possible drug target for treatment of cancer. Here, we use cryo-electron microscopy to describe the detailed molecular structure of the human CAK, revealing its architecture and the interactions between its regulatory elements. Additionally, we have obtained the structure of the CAK in complex with a small-molecule inhibitor.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 13, 2020.
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The cryo-electron microscopy structure of the human CDK-activating kinase
Basil J. Greber, Juan M. Perez-Bertoldi, Kif Lim, Anthony T. Iavarone, Daniel B. Toso, Eva Nogales
bioRxiv 2020.05.13.094755; doi: https://doi.org/10.1101/2020.05.13.094755
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The cryo-electron microscopy structure of the human CDK-activating kinase
Basil J. Greber, Juan M. Perez-Bertoldi, Kif Lim, Anthony T. Iavarone, Daniel B. Toso, Eva Nogales
bioRxiv 2020.05.13.094755; doi: https://doi.org/10.1101/2020.05.13.094755

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