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- EMDB-54890: Consensus map of ternary PROTAC-mediated complex consisting of Ce... -

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Basic information

Entry
Database: EMDB / ID: EMD-54890
TitleConsensus map of ternary PROTAC-mediated complex consisting of Cereblon, DDB1 and BRD4-BD1, non-covalently linked by JQ1-AcN
Map dataconsensus map
Sample
  • Complex: Ternary PROTAC-mediated complex consisting of Cereblon, DDB1 and BRD4-BD1, non-covalently linked by JQ1-AcN
Keywordsternary complex / PROTAC / cereblon / LIGASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.66 Å
AuthorsFischer G / Peter D / Arce-Solano S / Kessler D
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Am Chem Soc / Year: 2025
Title: Enzyme-Activated Sugar-Coated Bifunctional Degraders.
Authors: Qian Zhu / Gerhard Fischer / Steven S Cheng / N Connor Payne / Daniel Peter / Alison C Mody / Silvia Arce-Solano / Dacheng Shen / Zhi Lin / Ralph Mazitschek / Dirk Kessler / Christina M Woo /
Abstract: Targeted protein degradation with compounds like proteolysis targeting chimeras (PROTACs) directs disease-associated proteins to the E3 ligase ubiquitin-proteasome system for removal. However, ...Targeted protein degradation with compounds like proteolysis targeting chimeras (PROTACs) directs disease-associated proteins to the E3 ligase ubiquitin-proteasome system for removal. However, commonly employed E3 ligases such as cereblon (CRBN) are broadly expressed. To metabolically gate PROTAC activity, we developed an enzymatic activation strategy by integrating an O-GlcNAc modification to the cyclimids, ligands derived from the natural motifs recognized by CRBN. These sugar-coated PROTACs (SCPs) were designed using structural analyses of representative cyclimid degraders complexed with CRBN and target protein BRD4. We found that glycosylation of the cyclimid reduced CRBN binding and complex formation with BRD4 until enzymatic removal of the O-GlcNAc moiety by O-GlcNAcase (OGA). The requirement for enzymatic activation is demonstrated by biochemical binding, cellular degradation, and cell viability assays in engineered and native cell lines. O-GlcNAc is thus an effective mechanism to gate targeted protein degradation modalities that motivates the development of similar strategies to enhance selectivity with other protein modifications.
History
DepositionAug 25, 2025-
Header (metadata) releaseJul 29, 2026-
Map releaseJul 29, 2026-
UpdateJul 29, 2026-
Current statusJul 29, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54890.png

Downloads & links

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Map

FileDownload / File: emd_54890.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationconsensus map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 384 pix.
= 287.616 Å		0.75 Å/pix.
x 384 pix.
= 287.616 Å		0.75 Å/pix.
x 384 pix.
= 287.616 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.749 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.2729038 - 0.44297352
Average (Standard dev.)-0.00022872067 (±0.009785281)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 287.616 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half-map A

Fileemd_54890_half_map_1.map
AnnotationHalf-map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map B

Fileemd_54890_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 : Ternary PROTAC-mediated complex consisting of Cereblon, DDB1 and ...

EntireName: Ternary PROTAC-mediated complex consisting of Cereblon, DDB1 and BRD4-BD1, non-covalently linked by JQ1-AcN
Components
  • Complex: Ternary PROTAC-mediated complex consisting of Cereblon, DDB1 and BRD4-BD1, non-covalently linked by JQ1-AcN

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Supramolecule #1: Ternary PROTAC-mediated complex consisting of Cereblon, DDB1 and ...

SupramoleculeName: Ternary PROTAC-mediated complex consisting of Cereblon, DDB1 and BRD4-BD1, non-covalently linked by JQ1-AcN
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
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

Concentration0.3 mg/mL
BufferpH: 7.5
Component:
ConcentrationName
20.0 mMHEPES
100.0 mMNaCl
0.25 mMTCEP

Details: 20 mM HEPES, 100 mM NaCl, 0.25 mM TCEP, pH: 7.5
GridModel: UltrAuFoil R1.2/1.3 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
Detailscomplex purified via size exclusion chromatography

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 3 / Number real images: 21670 / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE / Details: ab-initio reconstruction (cryoSPARC)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.66 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 184507
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

3mxf

chain_id: A, source_name: PDB, initial_model_type: experimental model

5fqd

chain_id: A, source_name: PDB, initial_model_type: experimental model

5fqd

chain_id: B, source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 94

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