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2.5 angstrom-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942
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PIIS0006349521000473.pdf | Published version | 1.95 MB | Adobe PDF | View/Open |
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