8S0R

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

これはPDB形式変換不可エントリーです。

8S0R の概要

• エントリーDOI: 10.2210/pdb8s0r/pdb
• EMDBエントリー: 19627
• 分子名称: CDK-activating kinase assembly factor MAT1, Cyclin-H, Cyclin-dependent kinase 7, ... (5 entities in total)
• 機能のキーワード: kinase, covalent inhibitor, transcription, cell cycle
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 87907.77

構造登録者

Feng, J.,Koh, A.F.,Kotecha, A.,Greber, B.J. (登録日: 2024-02-14, 公開日: 2024-12-25, 最終更新日: 2025-07-09)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (2.4 Å)