High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design.
Loading...
Embargo End Date
ICR Authors
Authors
Cushing, VI
Koh, AF
Feng, J
Jurgaityte, K
Bondke, A
Kroll, SHB
Barbazanges, M
Scheiper, B
Bahl, AK
Barrett, AGM
Ali, S
Kotecha, A
Greber, BJ
Koh, AF
Feng, J
Jurgaityte, K
Bondke, A
Kroll, SHB
Barbazanges, M
Scheiper, B
Bahl, AK
Barrett, AGM
Ali, S
Kotecha, A
Greber, BJ
Document Type
Journal Article
Date
2024-03-13
Date Accepted
2024-02-23
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.
Citation
Nature Communications, 2024, 15 (1), pp. 2265 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Struct Biol DNA repair