2.5 angstrom-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942
File(s)PIIS0006349521000473.pdf (1.91 MB)
Published version
Author(s)
Greber, BJ
Remis, J
Ali, S
Nogales, E
Type
Journal Article
Abstract
The human CDK-activating kinase (CAK), composed of CDK7, cyclin H, and MAT1, is involved in the control of transcription initiation and the cell cycle. Because of these activities, it has been identified as a promising target for cancer chemotherapy. A number of CDK7 inhibitors have entered clinical trials, among them ICEC0942 (also known as CT7001). Structural information can aid in improving the affinity and specificity of such drugs or drug candidates, reducing side effects in patients. Here, we have determined the structure of the human CAK in complex with ICEC0942 at 2.5 Å-resolution using cryogenic electron microscopy. Our structure reveals conformational differences of ICEC0942 compared with previous X-ray crystal structures of the CDK2-bound complex, and highlights the critical ability of cryogenic electron microscopy to resolve structures of drug-bound protein complexes without the need to crystalize the protein target
Date Issued
2021-02-16
Online Publication Date
2022-03-31T15:01:08Z
Date Acceptance
2020-12-21
ISSN
0006-3495
Publisher
Biophysical Society
Start Page
677
End Page
686
Journal / Book Title
Biophysical Journal
Volume
120
Issue
4
Copyright Statement
© 2021 Biophysical Society. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/)
creativecommons.org/licenses/by/4.0/)
License URI
Identifier
https://www.cell.com/biophysj/fulltext/S0006-3495(21)00047-3
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000630950000009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Biophysics
BEAM-INDUCED MOTION
CRYO-EM
MAT1
ORIENTATION
TOOL
CAK
Cell Cycle
Cell Division
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases
Humans
Phosphorylation
Humans
Cyclin-Dependent Kinases
Cell Cycle
Cell Division
Phosphorylation
Cyclin-Dependent Kinase 2
Science & Technology
Life Sciences & Biomedicine
Biophysics
BEAM-INDUCED MOTION
CRYO-EM
MAT1
ORIENTATION
TOOL
CAK
Biophysics
02 Physical Sciences
03 Chemical Sciences
06 Biological Sciences
Publication Status
Published
Date Publish Online
2021-01-18