8S0R

Cryo-EM structure of CAK modified by covalent inhibitor SY-1365

This is a non-PDB format compatible entry.

Summary for 8S0R

• Entry DOI: 10.2210/pdb8s0r/pdb
• EMDB information: 19627
• Descriptor: CDK-activating kinase assembly factor MAT1, Cyclin-H, Cyclin-dependent kinase 7, ... (5 entities in total)
• Functional Keywords: kinase, covalent inhibitor, transcription, cell cycle
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 87907.77

Authors

Feng, J.,Koh, A.F.,Kotecha, A.,Greber, B.J. (deposition date: 2024-02-14, release date: 2024-12-25, Last modification date: 2025-07-09)

Primary citation

Jones, T.,Feng, J.,Luyties, O.,Cozzolino, K.,Sanford, L.,Rimel, J.K.,Ebmeier, C.C.,Shelby, G.S.,Watts, L.P.,Rodino, J.,Rajagopal, N.,Hu, S.,Brennan, F.,Maas, Z.L.,Alnemy, S.,Richter, W.F.,Koh, A.F.,Cronin, N.B.,Madduri, A.,Das, J.,Cooper, E.,Hamman, K.B.,Carulli, J.P.,Allen, M.A.,Spencer, S.,Kotecha, A.,Marineau, J.J.,Greber, B.J.,Dowell, R.D.,Taatjes, D.J.
TFIIH kinase CDK7 drives cell proliferation through a common core transcription factor network.
Sci Adv, 11:eadr9660-eadr9660, 2025

PubMed Abstract: How cyclin-dependent kinase 7 (CDK7) coordinately regulates the cell cycle and RNA polymerase II transcription remains unclear. Here, high-resolution cryo-electron microscopy revealed how two clinically relevant inhibitors block CDK7 function. In cells, CDK7 inhibition rapidly suppressed transcription, but constitutively active genes were disproportionately affected versus stimulus-responsive. Distinct transcription factors (TFs) regulate constitutive versus stimulus-responsive genes. Accordingly, stimulus-responsive TFs were refractory to CDK7 inhibition whereas constitutively active "core" TFs were repressed. Core TFs (n = 78) are predominantly promoter associated and control cell cycle and proliferative gene expression programs across cell types. Mechanistically, rapid suppression of core TF function can occur through CDK7-dependent phosphorylation changes in core TFs and RB1. Moreover, CDK7 inhibition depleted core TF protein levels within hours, consistent with durable target gene suppression. Thus, a major but unappreciated biological function for CDK7 is regulation of a TF cohort that drives proliferation, revealing an apparent universal mechanism by which CDK7 coordinates RNAPII transcription with cell cycle CDK regulation.

PubMed: 40020069
DOI: 10.1126/sciadv.adr9660

Experimental method

ELECTRON MICROSCOPY (2.4 Å)