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- EMDB-17542: Negative stain map of UBR5 (dimer) in complex with RARA/RXRA -

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Basic information

Entry
Database: EMDB / ID: EMD-17542
TitleNegative stain map of UBR5 (dimer) in complex with RARA/RXRA
Map dataHalf-map A.
Sample
  • Complex: UBR5 in complex with RARA/RXRA
    • Protein or peptide: UBR5
    • Protein or peptide: RARA
    • Protein or peptide: RXRA
KeywordsE3 / ubiquitin ligase / HECT / LIGASE
Function / homology
Function and homology information


Sertoli cell fate commitment / positive regulation of binding / heterochromatin boundary formation / trachea cartilage development / ventricular cardiac muscle cell differentiation / embryonic camera-type eye development / chondroblast differentiation / glandular epithelial cell development / negative regulation of granulocyte differentiation / protein kinase B binding ...Sertoli cell fate commitment / positive regulation of binding / heterochromatin boundary formation / trachea cartilage development / ventricular cardiac muscle cell differentiation / embryonic camera-type eye development / chondroblast differentiation / glandular epithelial cell development / negative regulation of granulocyte differentiation / protein kinase B binding / cellular response to corticotropin-releasing hormone stimulus / growth plate cartilage development / positive regulation of T-helper 2 cell differentiation / prostate gland development / negative regulation of cartilage development / positive regulation of transporter activity / retinoic acid-responsive element binding / NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis / NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose / regulation of hematopoietic progenitor cell differentiation / NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake / positive regulation of thyroid hormone receptor signaling pathway / positive regulation of interleukin-13 production / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / positive regulation of interleukin-5 production / nuclear glucocorticoid receptor binding / Carnitine metabolism / ion binding / HECT-type E3 ubiquitin transferase / Regulation of pyruvate dehydrogenase (PDH) complex / retinoic acid binding / response to vitamin A / positive regulation of vitamin D receptor signaling pathway / nuclear vitamin D receptor binding / apoptotic cell clearance / limb development / DNA repair-dependent chromatin remodeling / ubiquitin-ubiquitin ligase activity / regulation of myelination / protein kinase A binding / ureteric bud development / Signaling by Retinoic Acid / DNA binding domain binding / DNA-binding transcription repressor activity / nuclear steroid receptor activity / heterocyclic compound binding / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / positive regulation of interleukin-4 production / LBD domain binding / face development / progesterone receptor signaling pathway / alpha-actinin binding / germ cell development / negative regulation of type II interferon production / negative regulation of tumor necrosis factor production / Synthesis of bile acids and bile salts / positive regulation of cholesterol efflux / retinoic acid receptor signaling pathway / cellular response to estrogen stimulus / Endogenous sterols / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / protein K48-linked ubiquitination / positive regulation of bone mineralization / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / positive regulation of cell cycle / cellular response to retinoic acid / response to retinoic acid / Recycling of bile acids and salts / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / peroxisome proliferator activated receptor signaling pathway / RORA activates gene expression / positive regulation of neuron differentiation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / mRNA regulatory element binding translation repressor activity / BMAL1:CLOCK,NPAS2 activates circadian gene expression / negative regulation of miRNA transcription / Activation of gene expression by SREBF (SREBP) / liver development / ubiquitin binding / response to cytokine / neural tube closure / transcription coregulator binding / female pregnancy / hippocampus development / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / peptide binding / Heme signaling / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / regulation of synaptic plasticity / Transcriptional activation of mitochondrial biogenesis / multicellular organism growth / PPARA activates gene expression / Cytoprotection by HMOX1 / chromatin DNA binding / mRNA 5'-UTR binding / transcription coactivator binding / histone deacetylase binding
Similarity search - Function
: / E3 ubiquitin ligase EDD, ubiquitin-associated domain / E3 ubiquitin ligase EDD / Polyadenylate-binding protein/Hyperplastic disc protein / Poly(A)-binding protein C-terminal (PABC) domain profile. / C-terminal domain of Poly(A)-binding protein. Present also in Drosophila hyperplastics discs protein. / PABC (PABP) domain / : / : / Poly-adenylate binding protein, unique domain ...: / E3 ubiquitin ligase EDD, ubiquitin-associated domain / E3 ubiquitin ligase EDD / Polyadenylate-binding protein/Hyperplastic disc protein / Poly(A)-binding protein C-terminal (PABC) domain profile. / C-terminal domain of Poly(A)-binding protein. Present also in Drosophila hyperplastics discs protein. / PABC (PABP) domain / : / : / Poly-adenylate binding protein, unique domain / Zinc finger, UBR-type / Zinc finger UBR-type profile. / Putative zinc finger in N-recognin, a recognition component of the N-end rule pathway / Retinoic acid receptor / Regulator of chromosome condensation 1/beta-lactamase-inhibitor protein II / Nuclear/hormone receptor activator site AF-1 / Nuclear/hormone receptor activator site AF-1 / Retinoid X receptor/HNF4 / HECT domain / HECT, E3 ligase catalytic domain / HECT-domain (ubiquitin-transferase) / HECT domain profile. / Domain Homologous to E6-AP Carboxyl Terminus with / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type
Similarity search - Domain/homology
E3 ubiquitin-protein ligase UBR5 / Retinoic acid receptor alpha / Retinoic acid receptor RXR-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / negative staining / Resolution: 25.0 Å
AuthorsAguirre JD / Cavadini S / Kempf G / Kater L / Thoma NH
Funding support Switzerland, European Union, 3 items
OrganizationGrant numberCountry
Swiss National Science Foundation179541 Switzerland
Swiss National Science Foundation201206 Switzerland
European Research Council (ERC)884331European Union
CitationJournal: 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
DepositionMay 31, 2023-
Header (metadata) releaseJun 7, 2023-
Map releaseJun 7, 2023-
UpdateDec 27, 2023-
Current statusDec 27, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17542.png

Downloads & links

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Map

FileDownload / File: emd_17542.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHalf-map A.
Voxel sizeX=Y=Z: 2.2 Å
Density
Contour LevelBy AUTHOR: 1.9
Minimum - Maximum-0.4285514 - 3.2889066
Average (Standard dev.)-0.005750237 (±0.18206154)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 563.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Full-map.

Fileemd_17542_half_map_1.map
AnnotationFull-map.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map B.

Fileemd_17542_half_map_2.map
AnnotationHalf-map B.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : UBR5 in complex with RARA/RXRA

EntireName: UBR5 in complex with RARA/RXRA
Components
  • Complex: UBR5 in complex with RARA/RXRA
    • Protein or peptide: UBR5
    • Protein or peptide: RARA
    • Protein or peptide: RXRA

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Supramolecule #1: UBR5 in complex with RARA/RXRA

SupramoleculeName: UBR5 in complex with RARA/RXRA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: UBR5

MacromoleculeName: UBR5 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKL AAANSSIDLI STSLYKKAGF RTMTSIHFVV HPLPGTEDQL NDRLREVSEK LNKYNLNSHP PLNVLEQATI KQCVVGPNHA AFLLEDGRVC RIGFSVQPDR LELGKPDNND GSKLNSNSGA GRTSRPGRTS DSPWFLSGSE TLGRLAGNTL GSRWSSGVGG ...String:
MDYKDDDDKL AAANSSIDLI STSLYKKAGF RTMTSIHFVV HPLPGTEDQL NDRLREVSEK LNKYNLNSHP PLNVLEQATI KQCVVGPNHA AFLLEDGRVC RIGFSVQPDR LELGKPDNND GSKLNSNSGA GRTSRPGRTS DSPWFLSGSE TLGRLAGNTL GSRWSSGVGG SGGGSSGRSS AGARDSRRQT RVIRTGRDRG SGLLGSQPQP VIPASVIPEE LISQAQVVLQ GKSRSVIIRE LQRTNLDVNL AVNNLLSRDD EDGDDGDDTA SESYLPGEDL MSLLDADIHS AHPSVIIDAD AMFSEDISYF GYPSFRRSSL SRLGSSRVLL LPLERDSELL RERESVLRLR ERRWLDGASF DNERGSTSKE GEPNLDKKNT PVQSPVSLGE DLQWWPDKDG TKFICIGALY SELLAVSSKG ELYQWKWSES EPYRNAQNPS LHHPRATFLG LTNEKIVLLS ANSIRATVAT ENNKVATWVD ETLSSVASKL EHTAQTYSEL QGERIVSLHC CALYTCAQLE NSLYWWGVVP FSQRRKMLEK ARAKNKKPKS SAGKTGGTPK VPDCFQRTPK KLCIPEKTEI LAVNVDSKGV HAVLKTGNWV RYCIFDLATG KAEQENNFPT SSIAFLGQNE RNVAIFTAGQ ESPIILRDGN GTIYPMAKDC MGGIRDPDWL DLPPISSLGM GVHSLINLPA NSTIKKKAAV IIMAVEKQTL MQHILRCDYE ACRQYLMNLE QAVVLEQNLQ MLQTFISHRC DGNRNILHAC VSVCFPTSNK ETKEEEEAER SERNTFAERL SAVEAIANAI SVVSSNGPGN RAGSSSSRSL RLREMMRRSL RAAGLGRHEA GASSSDHQDP VSPPIAPPSW VPDPPAMDPD GDIDFILAPA VGSLTTAATG TGQGPSTSTI PGPSTEPSVV ESKDRKANAH FILKLLCDSV VLQPYLRELL SAKDARGMTP FMSAVSGRAY PAAITILETA QKIAKAEISS SEKEEDVFMG MVCPSGTNPD DSPLYVLCCN DTCSFTWTGA EHINQDIFEC RTCGLLESLC CCTECARVCH KGHDCKLKRT SPTAYCDCWE KCKCKTLIAG QKSARLDLLY RLLTATNLVT LPNSRGEHLL LFLVQTVARQ TVEHCQYRPP RIREDRNRKT ASPEDSDMPD HDLEPPRFAQ LALERVLQDW NALKSMIMFG SQENKDPLSA SSRIGHLLPE EQVYLNQQSG TIRLDCFTHC LIVKCTADIL LLDTLLGTLV KELQNKYTPG RREEAIAVTM RFLRSVARVF VILSVEMASS KKKNNFIPQP IGKCKRVFQA LLPYAVEELC NVAESLIVPV RMGIARPTAP FTLASTSIDA MQGSEELFSV EPLPPRPSSD QSSSSSQSQS SYIIRNPQQR RISQSQPVRG RDEEQDDIVS ADVEEVEVVE GVAGEEDHHD EQEEHGEENA EAEGQHDEHD EDGSDMELDL LAAAETESDS ESNHSNQDNA SGRRSVVTAA TAGSEAGASS VPAFFSEDDS QSNDSSDSDS SSSQSDDIEQ ETFMLDEPLE RTTNSSHANG AAQAPRSMQW AVRNTQHQRA ASTAPSSTST PAASSAGLIY IDPSNLRRSG TISTSAAAAA AALEASNASS YLTSASSLAR AYSIVIRQIS DLMGLIPKYN HLVYSQIPAA VKLTYQDAVN LQNYVEEKLI PTWNWMVSIM DSTEAQLRYG SALASAGDPG HPNHPLHASQ NSARRERMTA REEASLRTLE GRRRATLLSA RQGMMSARGD FLNYALSLMR SHNDEHSDVL PVLDVCSLKH VAYVFQALIY WIKAMNQQTT LDTPQLERKR TRELLELGID NEDSEHENDD DTNQSATLND KDDDSLPAET GQNHPFFRRS DSMTFLGCIP PNPFEVPLAE AIPLADQPHL LQPNARKEDL FGRPSQGLYS SSASSGKCLM EVTVDRNCLE VLPTKMSYAA NLKNVMNMQN RQKKEGEEQP VLPEETESSK PGPSAHDLAA QLKSSLLAEI GLTESEGPPL TSFRPQCSFM GMVISHDMLL GRWRLSLELF GRVFMEDVGA EPGSILTELG G

UniProtKB: E3 ubiquitin-protein ligase UBR5

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Macromolecule #2: RARA

MacromoleculeName: RARA / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MDSHHHHHHH HHHSGMSDSE VNQEAKPEVK PEVKPETHIN LKVSDGSSEI FFKIKKTTPL RRLMEAFAKR QGKEMDSLTF LYDGIEIQAD QTPEDLDMED NDIIEAHREQ IGGDENLYFQ SESYTLTPEV GELIEKVRKA HQETFPALCQ LGKYTTNNSS EQRVSLDIDL ...String:
MDSHHHHHHH HHHSGMSDSE VNQEAKPEVK PEVKPETHIN LKVSDGSSEI FFKIKKTTPL RRLMEAFAKR QGKEMDSLTF LYDGIEIQAD QTPEDLDMED NDIIEAHREQ IGGDENLYFQ SESYTLTPEV GELIEKVRKA HQETFPALCQ LGKYTTNNSS EQRVSLDIDL WDKFSELSTK CIIKTVEFAK QLPGFTTLTI ADQITLLKAA CLDILILRIC TRYTPEQDTM TFSDGLTLNR TQMHNAGFGP LTDLVFAFAN QLLPLEMDDA ETGLLSAICL ICGDRQDLEQ PDRVDMLQEP LLEALKVYVR KRRPSRPHMF PKMLMKITDL RSISAKGAER VITLKMEIPG SMPPLIQEML ENSEGLD

UniProtKB: Retinoic acid receptor alpha

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Macromolecule #3: RXRA

MacromoleculeName: RXRA / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MDSHHHHHHH HHHSGMSDSE VNQEAKPEVK PEVKPETHIN LKVSDGSSEI FFKIKKTTPL RRLMEAFAKR QGKEMDSLTF LYDGIEIQAD QTPEDLDMED NDIIEAHREQ IGGDENLYFQ SANEDMPVER ILEAELAVEP KTETYVEANM GLNPSSPNDP VTNICQAADK ...String:
MDSHHHHHHH HHHSGMSDSE VNQEAKPEVK PEVKPETHIN LKVSDGSSEI FFKIKKTTPL RRLMEAFAKR QGKEMDSLTF LYDGIEIQAD QTPEDLDMED NDIIEAHREQ IGGDENLYFQ SANEDMPVER ILEAELAVEP KTETYVEANM GLNPSSPNDP VTNICQAADK QLFTLVEWAK RIPHFSELPL DDQVILLRAG WNELLIASFS HRSIAVKDGI LLATGLHVHR NSAHSAGVGA IFDRVLTELV SKMRDMQMDK TELGCLRAIV LFNPDSKGLS NPAEVEALRE KVYASLEAYC KHKYPEQPGR FAKLLLRLPA LRSIGLKCLE HLFFFKLIGD TPIDTFLMEM LEAPHQMT

UniProtKB: Retinoic acid receptor RXR-alpha

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Experimental details

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Structure determination

Methodnegative staining, cryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.6
StainingType: NEGATIVE / Material: Uranyl Acetate
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TECNAI SPIRIT
Image recordingFilm or detector model: FEI EAGLE (4k x 4k) / Average electron dose: 500.0 e/Å2
Electron beamAcceleration voltage: 120 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Tecnai Spirit / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 25.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4) / Number images used: 6389
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT

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