+Open data
-Basic information
Entry | Database: PDB / ID: 8p82 | ||||||||||||
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Title | Cryo-EM structure of dimeric UBR5 | ||||||||||||
Components | E3 ubiquitin-protein ligase UBR5 | ||||||||||||
Keywords | LIGASE / E3 / ubiquitin ligase / HECT | ||||||||||||
Function / homology | Function and homology information cytoplasm protein quality control / heterochromatin boundary formation / cytoplasm protein quality control by the ubiquitin-proteasome system / protein K29-linked ubiquitination / nuclear protein quality control by the ubiquitin-proteasome system / HECT-type E3 ubiquitin transferase / protein K11-linked ubiquitination / DNA repair-dependent chromatin remodeling / ubiquitin-ubiquitin ligase activity / progesterone receptor signaling pathway ...cytoplasm protein quality control / heterochromatin boundary formation / cytoplasm protein quality control by the ubiquitin-proteasome system / protein K29-linked ubiquitination / nuclear protein quality control by the ubiquitin-proteasome system / HECT-type E3 ubiquitin transferase / protein K11-linked ubiquitination / DNA repair-dependent chromatin remodeling / ubiquitin-ubiquitin ligase activity / progesterone receptor signaling pathway / protein K48-linked ubiquitination / negative regulation of smoothened signaling pathway / ubiquitin binding / positive regulation of protein import into nucleus / protein polyubiquitination / positive regulation of canonical Wnt signaling pathway / ubiquitin protein ligase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA repair / DNA damage response / positive regulation of gene expression / chromatin / perinuclear region of cytoplasm / protein-containing complex / RNA binding / zinc ion binding / nucleoplasm / membrane / nucleus / cytoplasm / cytosol Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.36 Å | ||||||||||||
Authors | Aguirre, J.D. / Kater, L. / Kempf, G. / Cavadini, S. / Thoma, N.H. | ||||||||||||
Funding support | Switzerland, European Union, 3items
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Citation | Journal: Mol Cell / Year: 2023 Title: UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability. Authors: Jonathan M Tsai / Jacob D Aguirre / Yen-Der Li / Jared Brown / Vivian Focht / Lukas Kater / Georg Kempf / Brittany Sandoval / Stefan Schmitt / Justine C Rutter / Pius Galli / Colby R Sandate ...Authors: Jonathan M Tsai / Jacob D Aguirre / Yen-Der Li / Jared Brown / Vivian Focht / Lukas Kater / Georg Kempf / Brittany Sandoval / Stefan Schmitt / Justine C Rutter / Pius Galli / Colby R Sandate / Jevon A Cutler / Charles Zou / Katherine A Donovan / Ryan J Lumpkin / Simone Cavadini / Paul M C Park / Quinlan Sievers / Charlie Hatton / Elizabeth Ener / Brandon D Regalado / Micah T Sperling / Mikołaj Słabicki / Jeonghyeon Kim / Rebecca Zon / Zinan Zhang / Peter G Miller / Roger Belizaire / Adam S Sperling / Eric S Fischer / Rafael Irizarry / Scott A Armstrong / Nicolas H Thomä / Benjamin L Ebert / 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- ...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. | ||||||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8p82.cif.gz | 660.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8p82.ent.gz | 502.8 KB | Display | PDB format |
PDBx/mmJSON format | 8p82.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8p82_validation.pdf.gz | 1 MB | Display | wwPDB validaton report |
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Full document | 8p82_full_validation.pdf.gz | 1 MB | Display | |
Data in XML | 8p82_validation.xml.gz | 89.1 KB | Display | |
Data in CIF | 8p82_validation.cif.gz | 139.8 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/p8/8p82 ftp://data.pdbj.org/pub/pdb/validation_reports/p8/8p82 | HTTPS FTP |
-Related structure data
Related structure data | 17539MC 8p83C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 313263.688 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: UBR5, EDD, EDD1, HYD, KIAA0896 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) References: UniProt: O95071, HECT-type E3 ubiquitin transferase #2: Chemical | ChemComp-ZN / Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Dimer of UBR5 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.6 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||
3D reconstruction | Resolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 399325 / Symmetry type: POINT | |||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL |