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Cushing, Victoria I; Koh, Adrian F; Feng, Junjie; Jurgaityte, Kaste; Bondke, Alexander; Kroll, Sebastian H B; Barbazanges, Marion; Scheiper, Bodo; Bahl, Ash K; Barrett, Anthony G M; Ali, Simak; Kotecha, Abhay; Greber, Basil J
Nature communications, 03/2024, Volume: 15, Issue: 1Journal Article
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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