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- EMDB-55235: EloB/EloC/VHL/CV2a/14-3-3zeta/ERa pose 2.1 -

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Basic information

Entry
Database: EMDB / ID: EMD-55235
TitleEloB/EloC/VHL/CV2a/14-3-3zeta/ERa pose 2.1
Map data
Sample
  • Complex: 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
KeywordsE3 ligase / von Hippel-Lindau / VHL / Elongin C / Elongin B / 14-3-3 / estrogen receptor alpha / PROTAC / proteolysis targeted chimera / LIGASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.5 Å
AuthorsCrowe C / Nakasone MA / Harzing T / Verhoef CJA / Cossar PJ / Ciulli A
Funding supportEuropean Union, United Kingdom, 3 items
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, 2025-
Header (metadata) releaseDec 3, 2025-
Map releaseDec 3, 2025-
UpdateSep 2, 2026-
Current statusSep 2, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_55235.png

Downloads & links

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Map

FileDownload / File: emd_55235.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 248.7 Å		0.83 Å/pix.
x 300 pix.
= 248.7 Å		0.83 Å/pix.
x 300 pix.
= 248.7 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.829 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.0758
Minimum - Maximum-0.076211266 - 0.23748164
Average (Standard dev.)0.00084843143 (±0.00902651)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 248.7 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_55235_half_map_1.map
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Half map: #2

Fileemd_55235_half_map_2.map
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Sample components

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Entire : Quaternary complex of the VCB (VHL-EloC-EloB) E3 ligase von Hippe...

EntireName: 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
Components
  • Complex: 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

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Supramolecule #1: Quaternary complex of the VCB (VHL-EloC-EloB) E3 ligase von Hippe...

SupramoleculeName: 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 / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 33.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.7 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 6.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 192706
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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