{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Cushing VI"],"funding":["Cancer Research UK","Medical Research Council"],"pagination":["2265"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10937634"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["15(1)"],"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."],"journal":["Nature communications"],"pubmed_title":["High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design."],"pmcid":["PMC10937634"],"funding_grant_id":["C37/A12011","C37/A9335","C37/A18784","MR/V009354/1"],"pubmed_authors":["Cushing VI","Koh AF","Kroll SHB","Jurgaityte K","Greber BJ","Bahl AK","Barrett AGM","Feng J","Bondke A","Ali S","Kotecha A","Barbazanges M","Scheiper B"],"additional_accession":[]},"is_claimable":false,"name":"High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-07-15T13:55:37.719Z","creation":"2026-07-05T03:12:06.741Z"},"accession":"S-EPMC10937634","cross_references":{"pubmed":["38480681"],"doi":["10.1038/s41467-024-46375-9"]}}