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- EMDB-54194: ZZ1-SO2H-induced assembly of the YPEL5-CTLH E3 ligase and BRD4(BD... -

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Entry
Database: EMDB / ID: EMD-54194
TitleZZ1-SO2H-induced assembly of the YPEL5-CTLH E3 ligase and BRD4(BD1) neosubstrate
Map data
Sample
  • Complex: ZZ1-SO2H-induced complex of YPEL5-CTLH E3 ligase and the first bromodomain (BD1) of BRD4
KeywordsE3 ubiquitin ligase / CTLH / GID / YPEL5 / Molecular Glue Degrader / Targeted Protein Degradation / LIGASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 11.77 Å
AuthorsChrustowicz J / Schulman BA
Funding support Germany, European Union, 3 items
OrganizationGrant numberCountry
German Research Foundation (DFG)SCHU 3196/1-1 Germany
European Research Council (ERC)UPSmeetMet, 101098161European Union
Max Planck Society Germany
CitationJournal: Nat Chem Biol / Year: 2026
Title: Charged molecular glue discovery enabled by targeted degron display.
Authors: Zhe Zhuang / Woong Sub Byun / Jakub Chrustowicz / Zuzanna Kozicka / Veronica L Li / Dinah M Abeja / Katherine A Donovan / Sara Sepic / Inchul You / Mikołaj Słabicki / Eric S Fischer / ...Authors: Zhe Zhuang / Woong Sub Byun / Jakub Chrustowicz / Zuzanna Kozicka / Veronica L Li / Dinah M Abeja / Katherine A Donovan / Sara Sepic / Inchul You / Mikołaj Słabicki / Eric S Fischer / Stephen M Hinshaw / Benjamin L Ebert / Brenda A Schulman / Nathanael S Gray /
Abstract: Small molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways and tools for agriculture. Explosive growth of targeted protein degradation ...Small molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways and tools for agriculture. Explosive growth of targeted protein degradation drug development has spurred renewed interest in proximity-inducing molecules, especially molecular glue degraders (MGDs). These compounds catalyze the destruction of disease-causing proteins by reshaping protein surfaces and promoting cooperative binding between ubiquitylating enzymes and target proteins. MGD discovery for predefined targets is a major challenge in contemporary drug discovery. Here, we solve this important chemical challenge through 'chemocentric' MGD discovery of ZZ1, a BET-family protein degrader and a prodrug of a negatively charged glue. ZZ1 activation unmasks a sulfinic acid that binds the modular CTLH ubiquitin ligase complex through a basic pocket in its YPEL5 subunit. These findings demonstrate a previously unrecognized capacity of YPEL5 to recruit CTLH substrates and enable the discovery of MGDs for exceedingly common acidic and basic degrons.
History
DepositionJun 27, 2025-
Header (metadata) releaseApr 8, 2026-
Map releaseApr 8, 2026-
UpdateApr 29, 2026-
Current statusApr 29, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54194.png

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Map

FileDownload / File: emd_54194.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
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Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
3.4 Å/pix.
x 128 pix.
= 435.802 Å		3.4 Å/pix.
x 128 pix.
= 435.802 Å		3.4 Å/pix.
x 128 pix.
= 435.802 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 3.4047 Å
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Contour LevelBy AUTHOR: 0.0534
Minimum - Maximum-0.04178166 - 0.15721674
Average (Standard dev.)0.001955759 (±0.012213161)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions128128128
Spacing128128128
CellA=B=C: 435.8016 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_54194_msk_1.map
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Half map: #1

Fileemd_54194_half_map_1.map
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Half map: #2

Fileemd_54194_half_map_2.map
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Sample components

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Entire : ZZ1-SO2H-induced complex of YPEL5-CTLH E3 ligase and the first br...

EntireName: ZZ1-SO2H-induced complex of YPEL5-CTLH E3 ligase and the first bromodomain (BD1) of BRD4
Components
  • Complex: ZZ1-SO2H-induced complex of YPEL5-CTLH E3 ligase and the first bromodomain (BD1) of BRD4

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Supramolecule #1: ZZ1-SO2H-induced complex of YPEL5-CTLH E3 ligase and the first br...

SupramoleculeName: ZZ1-SO2H-induced complex of YPEL5-CTLH E3 ligase and the first bromodomain (BD1) of BRD4
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: The YPEL5-CTLH complex consists of TWA1, RANBP9, RMND5A, MAEA, WDR26, and YPEL5.
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1 MDa

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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

Concentration2.5 mg/mL
BufferpH: 7.5
VitrificationCryogen name: NITROGEN
DetailsSample mixed with 0.1% beta-OG right before plunging

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 65.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 893388
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

18170

Final reconstructionResolution.type: BY AUTHOR / Resolution: 11.77 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 2464
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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