2.5 Å-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942.
Journal
Biophysical journal
ISSN: 1542-0086
Titre abrégé: Biophys J
Pays: United States
ID NLM: 0370626
Informations de publication
Date de publication:
16 02 2021
16 02 2021
Historique:
received:
05
11
2020
revised:
11
12
2020
accepted:
21
12
2020
pubmed:
22
1
2021
medline:
1
6
2021
entrez:
21
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33476598
pii: S0006-3495(21)00047-3
doi: 10.1016/j.bpj.2020.12.030
pmc: PMC7896097
pii:
doi:
Substances chimiques
Cyclin-Dependent Kinase 2
EC 2.7.11.22
Cyclin-Dependent Kinases
EC 2.7.11.22
Cyclin-Dependent Kinase-Activating Kinase
EC 2.7.11.22
CDK7 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
677-686Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM127018
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : Cancer Research UK
ID : C37/A18784
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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