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Article Dans Une Revue Nature Communications Année : 2024

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

Adrian F Koh
Kaste Jurgaityte
Ash K Bahl
  • Fonction : Auteur
Anthony G M Barrett
Simak Ali
Abhay Kotecha

Résumé

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.
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Licence : CC BY - Paternité

Dates et versions

hal-04506209 , version 1 (15-03-2024)

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Paternité

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Victoria I Cushing, Adrian F Koh, Junjie Feng, Kaste Jurgaityte, Alexander Bondke, et al.. High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design. Nature Communications, 2024, 15 (1), pp.2265. ⟨10.1038/s41467-024-46375-9⟩. ⟨hal-04506209⟩
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