8P75
Cryo-EM structure of CAK in complex with inhibitor ICEC0880 (ring-down conformation)
Summary for 8P75
| Entry DOI | 10.2210/pdb8p75/pdb |
| EMDB information | 17129 17518 |
| Descriptor | CDK-activating kinase assembly factor MAT1, Cyclin-H, Cyclin-dependent kinase 7, ... (5 entities in total) |
| Functional Keywords | kinase, inhibitor, transcription, cell cycle, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 87782.99 |
| Authors | Cushing, V.I.,Koh, A.F.,Feng, J.,Jurgaityte, K.,Bahl, A.K.,Ali, S.,Kotecha, A.,Greber, B.J. (deposition date: 2023-05-30, release date: 2024-03-20, Last modification date: 2024-03-27) |
| Primary citation | Cushing, V.I.,Koh, A.F.,Feng, J.,Jurgaityte, K.,Bondke, A.,Kroll, S.H.B.,Barbazanges, M.,Scheiper, B.,Bahl, A.K.,Barrett, A.G.M.,Ali, S.,Kotecha, A.,Greber, B.J. High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design. Nat Commun, 15:2265-2265, 2024 Cited by 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. PubMed: 38480681DOI: 10.1038/s41467-024-46375-9 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2 Å) |
Structure validation
Download full validation report
