8P77

Cryo-EM structure of CAK in complex with inhibitor ICEC0943

Summary for 8P77

• Entry DOI: 10.2210/pdb8p77/pdb
• Related: 8ORM
• EMDB information: 17129 17520
• Descriptor: CDK-activating kinase assembly factor MAT1, Cyclin-H, Cyclin-dependent kinase 7, ... (5 entities in total)
• Functional Keywords: kinase, inhibitor, transcription, cell cycle, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 87713.15

Authors

Cushing, V.I.,Koh, A.F.,Feng, J.,Jurgaityte, K.,Bahl, A.K.,Ali, S.,Kotecha, A.,Greber, B.J. (deposition date: 2023-05-30, release date: 2024-03-20, Last modification date: 2024-10-16)

Primary citation

Cushing, V.I.,Koh, A.F.,Feng, J.,Jurgaityte, K.,Bondke, A.,Kroll, S.H.B.,Barbazanges, M.,Scheiper, B.,Bahl, A.K.,Barrett, A.G.M.,Ali, S.,Kotecha, A.,Greber, B.J.
High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design.
Nat Commun, 15:2265-2265, 2024

PubMed Abstract: Rational design of next-generation therapeutics can be facilitated by high-resolution structures of drug targets bound to small-molecule inhibitors. However, application of structure-based methods to macromolecules refractory to crystallization has been hampered by the often-limiting resolution and throughput of cryogenic electron microscopy (cryo-EM). Here, we use high-resolution cryo-EM to determine structures of the CDK-activating kinase, a master regulator of cell growth and division, in its free and nucleotide-bound states and in complex with 15 inhibitors at up to 1.8 Å resolution. Our structures provide detailed insight into inhibitor interactions and networks of water molecules in the active site of cyclin-dependent kinase 7 and provide insights into the mechanisms contributing to inhibitor selectivity, thereby providing the basis for rational design of next-generation therapeutics. These results establish a methodological framework for the use of high-resolution cryo-EM in structure-based drug design.

PubMed: 38480681
DOI: 10.1038/s41467-024-46375-9

Experimental method

ELECTRON MICROSCOPY (1.8 Å)