High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design

Victoria I. Cushing, Adrian F. Koh, Junjie Feng, Kaste Jurgaityte, Alexander Bondke, Sebastian H. B. Kroll, Marion Barbazanges, Bodo Scheiper, Ash K. Bahl, Anthony G. M. Barrett, Simak Ali (), Abhay Kotecha () and Basil J. Greber ()
Additional contact information
Victoria I. Cushing: Chester Beatty Laboratories
Adrian F. Koh: Thermo Fisher Scientific
Junjie Feng: Chester Beatty Laboratories
Kaste Jurgaityte: Hammersmith Hospital Campus
Alexander Bondke: Imperial College London
Sebastian H. B. Kroll: Imperial College London
Marion Barbazanges: Imperial College London
Bodo Scheiper: Imperial College London
Ash K. Bahl: Nova UCD
Anthony G. M. Barrett: Imperial College London
Simak Ali: Hammersmith Hospital Campus
Abhay Kotecha: Thermo Fisher Scientific
Basil J. Greber: Chester Beatty Laboratories

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46375-9

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