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2.5 angstrom-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942

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Title: 2.5 angstrom-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942
Authors: Greber, BJ
Remis, J
Ali, S
Nogales, E
Item 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
Issue Date: 16-Feb-2021
Date of Acceptance: 21-Dec-2020
URI: http://hdl.handle.net/10044/1/96066
DOI: 10.1016/j.bpj.2020.12.030
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/)
Keywords: 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
Online Publication Date: 2021-01-18
Appears in Collections:Department of Surgery and Cancer



This item is licensed under a Creative Commons License Creative Commons