8p72

Cryo-EM structure of CAK in complex with inhibitor ICEC0768

spinqualitylabelsall models 8p72, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8p72 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 1.9Å Ligands: ACE, X2Z Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MAT1_HUMAN Stabilizes the cyclin H-CDK7 complex to form a functional CDK-activating kinase (CAK) enzymatic complex. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminus domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Involved in cell cycle control and in RNA transcription by RNA polymerase II. Publication Abstract from PubMed 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 A 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. High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design.,Cushing VI, Koh AF, Feng J, Jurgaityte K, Bondke A, Kroll SHB, Barbazanges M, Scheiper B, Bahl AK, Barrett AGM, Ali S, Kotecha A, Greber BJ Nat Commun. 2024 Mar 13;15(1):2265. doi: 10.1038/s41467-024-46375-9. PMID:38480681 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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