8PYR

Crystal structure of the dual T-loop phosphorylated Cdk7/CycH/Mat1 complex

8PYR の概要

• エントリーDOI: 10.2210/pdb8pyr/pdb
• 分子名称: Cyclin-dependent kinase 7, Cyclin-H, CDK-activating kinase assembly factor MAT1, ... (6 entities in total)
• 機能のキーワード: cdk7, cyclin h, mat1, cdk activating kinase, kinase, phosphorylation, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 197237.91

構造登録者

Anand, K.,Duster, R.,Geyer, M. (登録日: 2023-07-26, 公開日: 2024-03-06, 最終更新日: 2025-04-30)

主引用文献

Duster, R.,Anand, K.,Binder, S.C.,Schmitz, M.,Gatterdam, K.,Fisher, R.P.,Geyer, M.
Structural basis of Cdk7 activation by dual T-loop phosphorylation.
Nat Commun, 15:6597-6597, 2024

PubMed Abstract: Cyclin-dependent kinase 7 (Cdk7) is required in cell-cycle and transcriptional regulation owing to its function as both a CDK-activating kinase (CAK) and part of transcription factor TFIIH. Cdk7 forms active complexes by associating with Cyclin H and Mat1, and is regulated by two phosphorylations in the activation segment (T loop): the canonical activating modification at T170 and another at S164. Here we report the crystal structure of the human Cdk7/Cyclin H/Mat1 complex containing both T-loop phosphorylations. Whereas pT170 coordinates basic residues conserved in other CDKs, pS164 nucleates an arginine network unique to the ternary Cdk7 complex, involving all three subunits. We identify differential dependencies of kinase activity and substrate recognition on the individual phosphorylations. CAK function is unaffected by T-loop phosphorylation, whereas activity towards non-CDK substrates is increased several-fold by T170 phosphorylation. Moreover, dual T-loop phosphorylation stimulates multisite phosphorylation of the RNA polymerase II (RNAPII) carboxy-terminal domain (CTD) and SPT5 carboxy-terminal repeat (CTR) region. In human cells, Cdk7 activation is a two-step process wherein S164 phosphorylation precedes, and may prime, T170 phosphorylation. Thus, dual T-loop phosphorylation can regulate Cdk7 through multiple mechanisms, with pS164 supporting tripartite complex formation and possibly influencing processivity, while pT170 enhances activity towards key transcriptional substrates.

PubMed: 39097586
DOI: 10.1038/s41467-024-50891-z

実験手法

X-RAY DIFFRACTION (2.15 Å)