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- EMDB-54895: Focus map of ternary PROTAC-mediated complex of BRD4-BD1/CRBN/DDB... -

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Basic information

Entry
Database: EMDB / ID: EMD-54895
TitleFocus map of ternary PROTAC-mediated complex of BRD4-BD1/CRBN/DDB1 and JQ1-AcQ bifunctional degrader
Map datafocus map for deposition D_1292150008;
Sample
  • Complex: PROTAC-mediated complex of DDB1 (BPB deletion), CRBN and BRD4 BD1 domain
    • Complex: Ligase sub-complex consisting of DDB1 (BPB deletion) and CRBN
    • Complex: degradation target BRD4 (BD1 domain)
KeywordsCryo-EM DDB1 (DNA Damage-Binding Protein 1) CRBN (Cereblon) BRD4 (bromodomain containing 4) Protein degradation cyclimid PROTACs / LIGASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.85 Å
AuthorsPeter D / Fischer G / 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 26, 2025-
Header (metadata) releaseOct 1, 2025-
Map releaseOct 1, 2025-
UpdateOct 1, 2025-
Current statusOct 1, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54895.png

Downloads & links

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Map

FileDownload / File: emd_54895.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationfocus map for deposition D_1292150008;
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: 0.04
Minimum - Maximum-0.11268924 - 0.20857054
Average (Standard dev.)-0.00006813784 (±0.0026077183)
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: #2

Fileemd_54895_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_54895_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : PROTAC-mediated complex of DDB1 (BPB deletion), CRBN and BRD4 BD1...

EntireName: PROTAC-mediated complex of DDB1 (BPB deletion), CRBN and BRD4 BD1 domain
Components
  • Complex: PROTAC-mediated complex of DDB1 (BPB deletion), CRBN and BRD4 BD1 domain
    • Complex: Ligase sub-complex consisting of DDB1 (BPB deletion) and CRBN
    • Complex: degradation target BRD4 (BD1 domain)

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Supramolecule #1: PROTAC-mediated complex of DDB1 (BPB deletion), CRBN and BRD4 BD1...

SupramoleculeName: PROTAC-mediated complex of DDB1 (BPB deletion), CRBN and BRD4 BD1 domain
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15 KDa

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Supramolecule #2: Ligase sub-complex consisting of DDB1 (BPB deletion) and CRBN

SupramoleculeName: Ligase sub-complex consisting of DDB1 (BPB deletion) and CRBN
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: degradation target BRD4 (BD1 domain)

SupramoleculeName: degradation target BRD4 (BD1 domain) / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #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:
ConcentrationFormulaName
20.0 mMHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
100.0 mMNaClsodium chloride
0.25 mMTCEPTris(2-carboxyethyl)phosphine
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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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: FEI FALCON IV (4k x 4k) / Number grids imaged: 3 / Number real images: 38923 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / 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 correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 158212
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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