8P82

Cryo-EM structure of dimeric UBR5

Summary for 8P82

• Entry DOI: 10.2210/pdb8p82/pdb
• EMDB information: 17539
• Descriptor: E3 ubiquitin-protein ligase UBR5, ZINC ION (2 entities in total)
• Functional Keywords: e3, ubiquitin ligase, hect, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 626919.83

Authors

Aguirre, J.D.,Kater, L.,Kempf, G.,Cavadini, S.,Thoma, N.H. (deposition date: 2023-05-31, release date: 2023-06-14, Last modification date: 2024-06-26)

Primary citation

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, 83:2753-2767.e10, 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

Experimental method

ELECTRON MICROSCOPY (3.36 Å)