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- PDB-9sv3: Local refinement of EloB/EloC/VHL/CV2a/14-3-3zeta/ERa from pose 1 -

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Basic information

Entry
Database: PDB / ID: 9sv3
TitleLocal refinement of EloB/EloC/VHL/CV2a/14-3-3zeta/ERa from pose 1
Components
  • 14-3-3 protein zeta/delta
  • Elongin-B
  • Elongin-C
  • Estrogen receptor
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / E3 ligase / von Hippel-Lindau / VHL / 14-3-3 / estrogen receptor alpha / PROTAC / proteolysis targeting chimera / degrader
Function / homology
Function and homology information


synaptic target recognition / Golgi reassembly / NOTCH4 Activation and Transmission of Signal to the Nucleus / respiratory system process / regulation of cellular response to hypoxia / establishment of Golgi localization / tube formation / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / regulation of synapse maturation ...synaptic target recognition / Golgi reassembly / NOTCH4 Activation and Transmission of Signal to the Nucleus / respiratory system process / regulation of cellular response to hypoxia / establishment of Golgi localization / tube formation / negative regulation of receptor signaling pathway via JAK-STAT / RHOBTB3 ATPase cycle / regulation of synapse maturation / Rap1 signalling / target-directed miRNA degradation / elongin complex / Replication of the SARS-CoV-1 genome / transcription elongation factor activity / regulation of epithelial cell apoptotic process / epithelial cell development / negative regulation of protein localization to nucleus / epithelial cell proliferation involved in mammary gland duct elongation / steroid hormone receptor signaling pathway / antral ovarian follicle growth / regulation of branching involved in prostate gland morphogenesis / KSRP (KHSRP) binds and destabilizes mRNA / : / VCB complex / Cul5-RING ubiquitin ligase complex / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / GP1b-IX-V activation signalling / uterus development / prostate epithelial cord elongation / nuclear estrogen receptor activity / regulation of toll-like receptor signaling pathway / vagina development / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / mammary gland branching involved in pregnancy / Cul2-RING ubiquitin ligase complex / mammary gland alveolus development / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / SUMOylation of ubiquitinylation proteins / : / negative regulation of transcription elongation by RNA polymerase II / androgen metabolic process / TFIIB-class transcription factor binding / negative regulation of smooth muscle cell apoptotic process / Regulation of localization of FOXO transcription factors / nuclear receptor-mediated steroid hormone signaling pathway / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / Interleukin-3, Interleukin-5 and GM-CSF signaling / lung development / cellular response to estrogen stimulus / estrogen response element binding / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / Mitochondrial unfolded protein response (UPRmt) / negative regulation of signal transduction / regulation of ERK1 and ERK2 cascade / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Nuclear signaling by ERBB4 / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / cellular response to glucose starvation / RNA polymerase II preinitiation complex assembly / Formation of HIV elongation complex in the absence of HIV Tat / estrogen receptor signaling pathway / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / ubiquitin-like ligase-substrate adaptor activity / positive regulation of nitric-oxide synthase activity / RNA Polymerase II Transcription Elongation / steroid binding / fibroblast proliferation / Formation of RNA Pol II elongation complex / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / negative regulation of TORC1 signaling / protein localization to chromatin / 14-3-3 protein binding / RNA Polymerase II Pre-transcription Events / Transcriptional and post-translational regulation of MITF-M expression and activity / ESR-mediated signaling / negative regulation of miRNA transcription / negative regulation of innate immune response / negative regulation of autophagy / TBP-class protein binding / stem cell differentiation / nitric-oxide synthase regulator activity / nuclear estrogen receptor binding / transcription corepressor binding / negative regulation of canonical NF-kappaB signal transduction / hippocampal mossy fiber to CA3 synapse / transcription coregulator binding / protein serine/threonine kinase binding / TP53 Regulates Metabolic Genes / cellular response to estradiol stimulus / SUMOylation of intracellular receptors / Translocation of SLC2A4 (GLUT4) to the plasma membrane
Similarity search - Function
von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Elongin-C / Elongin B ...von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Elongin-C / Elongin B / Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Estrogen receptor/oestrogen-related receptor / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain / 14-3-3 domain superfamily / 14-3-3 protein / : / SKP1/BTB/POZ domain superfamily / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Double treble clef zinc finger, C4 type / 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 / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
: / Estrogen receptor / von Hippel-Lindau disease tumor suppressor / 14-3-3 protein zeta/delta / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsCrowe, C. / Nakasone, M.A. / Harzing, T. / Verhoef, C.J.A. / Cossar, P.J. / Ciulli, A.
Funding supportEuropean Union, United Kingdom, 3items
OrganizationGrant numberCountry
European Research Council (ERC)ERC-2012-StG-311460 DrugE3CRLsEuropean Union
European Research Council (ERC)875510European Union
Medical Research Council (MRC, United Kingdom)MR/R015791/1 United Kingdom
CitationJournal: Nat Commun / Year: 2026
Title: Induced ubiquitination of the partially disordered estrogen receptor alpha via a 14-3-3 directed molecular glue-PROTAC.
Authors: Carlo J A Verhoef / Charlotte Crowe / Mark A Nakasone / Aitana DeLaCuadra-Basté / Tessa Harzing / Naomi A S Span / Gajanan Sathe / Laura C Demmers / Kentaro Iso / Christian Ottmann / Luc ...Authors: Carlo J A Verhoef / Charlotte Crowe / Mark A Nakasone / Aitana DeLaCuadra-Basté / Tessa Harzing / Naomi A S Span / Gajanan Sathe / Laura C Demmers / Kentaro Iso / Christian Ottmann / Luc Brunsveld / Alessio Ciulli / Peter J Cossar /
Abstract: Proteins lacking defined ligandable pockets remain challenging drug targets. Here, we develop a molecular glue-based PROTAC (PROTAC) approach that chemically conjugates a molecular glue stabilizer to ...Proteins lacking defined ligandable pockets remain challenging drug targets. Here, we develop a molecular glue-based PROTAC (PROTAC) approach that chemically conjugates a molecular glue stabilizer to a VHL-recruiting ligand to capture and ubiquitinate the 14-3-3/Estrogen receptor α (ERα) complex. Our designed PROTACs engage a composite interface between 14-3-3 and the disordered F-domain of ERα, promoting cooperative complex formation and targeted ubiquitination. Biophysical characterization revealed distinct linker-dependent cooperativities across the PROTAC series, which influenced both cellular permeability and ubiquitination efficiency. Cryo-EM of the most cooperative PROTAC uncovered de novo VHL-14-3-3ζ contacts, while molecular dynamics simulations rationalize the stabilizing interactions underlying cooperativity. Strikingly, fine-tuning linker design enables selective ubiquitination of distinct complex subunits. These findings establish a structural and mechanistic framework for integrating molecular glue and PROTAC principles, expanding the scope of drug discovery to previously intractable protein complexes.
History
DepositionSep 30, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 3, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Elongin-C
C: Elongin-B
G: Estrogen receptor
H: Estrogen receptor
I: 14-3-3 protein zeta/delta
D: 14-3-3 protein zeta/delta
E: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)191,3218
Polymers190,0867
Non-polymers1,2351
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 5 types, 7 molecules BCGHIDE

#1: Protein Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 10974.616 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369
#2: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 11748.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#3: Protein Estrogen receptor / ER / ER-alpha / Estradiol receptor / Nuclear receptor subfamily 3 group A member 1


Mass: 45511.188 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ESR1, ESR, NR3A1 / Production host: Escherichia coli (E. coli) / References: UniProt: P03372
#4: Protein 14-3-3 protein zeta/delta / Protein kinase C inhibitor protein 1 / KCIP-1


Mass: 28819.236 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YWHAZ / Production host: Escherichia coli (E. coli) / References: UniProt: P63104
#5: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18702.291 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli (E. coli) / References: UniProt: P40337

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Non-polymers , 1 types, 1 molecules

#6: Chemical ChemComp-A1JQT / ~{N}'-[(2~{S})-3,3-dimethyl-1-[(2~{S},4~{R})-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]-4-oxidanyl-pyrrolidin-1-yl]-1-oxidanylidene-butan-2-yl]-~{N}-[(2~{S})-2-[(1~{E},3~{R},4~{S},8~{R},9~{R},10~{R},11~{S},14~{S})-14-(methoxymethyl)-3,10-dimethyl-8-[(2~{S},3~{R},4~{S},5~{S},6~{R})-6-(2-methylbut-3-en-2-yloxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-4,9-bis(oxidanyl)-6-tricyclo[9.3.0.0^{3,7}]tetradeca-1,6-dienyl]propyl]tridecanediamide


Mass: 1234.625 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C67H103N5O14S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Quaternary complex of the VCB (VHL-EloC-EloB) E3 ligase von Hippel-Lindau substrate receptor in complex with small molecule CV2a, 14-3-3zeta and the estrogen receptor alpha
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESHEPES1
2100 mMsodium chlorideNaCl1
30.5 mMTCEPTCEP1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2700 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Image recordingElectron dose: 33 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1crYOLOparticle selection
4cryoSPARCCTF correction
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 140642 / Symmetry type: POINT

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