EMD-17542

Single-particle
25.0 Å
EMD-17542 Deposition: 31/05/2023
Map released: 07/06/2023
Last modified: 27/12/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-17542

Negative stain map of UBR5 (dimer) in complex with RARA/RXRA

EMD-17542

Single-particle
25.0 Å
EMD-17542 Deposition: 31/05/2023
Map released: 07/06/2023
Last modified: 27/12/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: UBR5 in complex with RARA/RXRA

Deposition Authors: Aguirre JD , Cavadini S, Kempf G, Kater L, Thoma NH
UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.
PUBMED: 37478846
DOI: doi:10.1016/j.molcel.2023.06.028
ISSN: 1097-2765
ASTM: MOCEFL
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.