8P83

Cryo-EM structure of full-length human UBR5 (homotetramer)

8P83 の概要

• エントリーDOI: 10.2210/pdb8p83/pdb
• EMDBエントリー: 17540
• 分子名称: E3 ubiquitin-protein ligase UBR5 (1 entity in total)
• 機能のキーワード: e3, ubiquitin ligase, hect, ligase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 1253054.75

構造登録者

Aguirre, J.D.,Kater, L.,Kempf, G.,Cavadini, S.,Thoma, N.H. (登録日: 2023-05-31, 公開日: 2023-06-14, 最終更新日: 2023-08-16)

主引用文献

Tsai, J.M.,Aguirre, J.D.,Li, Y.D.,Brown, J.,Focht, V.,Kater, L.,Kempf, G.,Sandoval, B.,Schmitt, S.,Rutter, J.C.,Galli, P.,Sandate, C.R.,Cutler, J.A.,Zou, C.,Donovan, K.A.,Lumpkin, R.J.,Cavadini, S.,Park, P.M.C.,Sievers, Q.,Hatton, C.,Ener, E.,Regalado, B.D.,Sperling, M.T.,Slabicki, M.,Kim, J.,Zon, R.,Zhang, Z.,Miller, P.G.,Belizaire, R.,Sperling, A.S.,Fischer, E.S.,Irizarry, R.,Armstrong, S.A.,Thoma, N.H.,Ebert, B.L.
UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.
Mol.Cell, 83:2753-, 2023

PubMed Abstract: Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription.

PubMed: 37478846
DOI: 10.1016/j.molcel.2023.06.028

実験手法

ELECTRON MICROSCOPY (3.87 Å)