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- EMDB-71617: Cryo-EM map of BRD9-ZZ7-DCAF16/DDB1/DDA1 ternary complex -

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Basic information

Entry
Database: EMDB / ID: EMD-71617
TitleCryo-EM map of BRD9-ZZ7-DCAF16/DDB1/DDA1 ternary complex
Map dataMain map
Sample
  • Complex: Ternary complex of BRD9-ZZ7-DCAF16/DDB1/DDA1
Keywordstargeted protein degradation / bromodomain / inhibitor / molecular glue / covalent / DCAF / E3 ligase / LIGASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.16 Å
AuthorsJin C / Baek K / Fischer E
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA214608-09 United States
CitationJournal: J Am Chem Soc / Year: 2025
Title: Discovery of BRD9 Molecular Glue Degraders That Spare Cardiomyocytes.
Authors: Woong Sub Byun / Zhe Zhuang / Anna P Hnatiuk / Cyrus Jin / Zixuan Jiang / Kheewoong Baek / Evelyn Chao / Katherine A Donovan / Eric S Fischer / Mark Mercola / Nathanael S Gray /
Abstract: Molecular glue degraders (MGDs) represent a class of drug-like small molecules that induce targeted protein degradation (TPD) by promoting selective protein-protein interactions. MGDs offer a ...Molecular glue degraders (MGDs) represent a class of drug-like small molecules that induce targeted protein degradation (TPD) by promoting selective protein-protein interactions. MGDs offer a promising therapeutic approach by selectively eliminating disease-associated proteins; however, their rational design and discovery have historically remained a significant challenge. The field remains constrained by a lack of strategies to effectively utilize ubiquitin ligases (E3s) for TPD, thus missing the therapeutic potential offered by tissue-specific E3 expression. In this study, we developed ZZ7, a molecular glue degrader that selectively degrades BRD9, a critical component of the SWI/SNF chromatin remodeling complex, specifically in synovial sarcoma cells, while sparing cardiomyocytes. The discovery of ZZ7 was driven by a "chemocentric" approach, incorporating a cysteine-reactive, reversible covalent warhead into a BRD9 inhibitor to transform its function from inhibition to degradation. ZZ7 covalently engages DCAF16 at Cys178, an E3 ligase that is highly expressed in synovial sarcoma cells but relatively underexpressed in human iPSC-derived cardiomyocytes, leveraging a cysteine residue that has not been previously exploited. These findings pave the way for new strategies in tissue- and disease-specific precision therapies, particularly for malignancies characterized by an elevated level of DCAF16 expression.
History
DepositionJul 7, 2025-
Header (metadata) releaseSep 24, 2025-
Map releaseSep 24, 2025-
UpdateApr 15, 2026-
Current statusApr 15, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71617.png

Downloads & links

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Map

FileDownload / File: emd_71617.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMain map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 512 pix.
= 376.832 Å		0.74 Å/pix.
x 512 pix.
= 376.832 Å		0.74 Å/pix.
x 512 pix.
= 376.832 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.736 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.055
Minimum - Maximum-0.23502341 - 0.41911215
Average (Standard dev.)0.00024579605 (±0.006614814)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 376.832 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_71617_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Sharpened map

Fileemd_71617_additional_1.map
AnnotationSharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1 for the main map

Fileemd_71617_half_map_1.map
AnnotationHalf map 1 for the main map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2 for the main map

Fileemd_71617_half_map_2.map
AnnotationHalf map 2 for the main 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 : Ternary complex of BRD9-ZZ7-DCAF16/DDB1/DDA1

EntireName: Ternary complex of BRD9-ZZ7-DCAF16/DDB1/DDA1
Components
  • Complex: Ternary complex of BRD9-ZZ7-DCAF16/DDB1/DDA1

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Supramolecule #1: Ternary complex of BRD9-ZZ7-DCAF16/DDB1/DDA1

SupramoleculeName: Ternary complex of BRD9-ZZ7-DCAF16/DDB1/DDA1 / 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: 7.4
Component:
ConcentrationFormulaName
30.0 mMC8H18N2O4SHEPES
200.0 mMNaClsodium chloride
2.0 mMC9H15O6PTCEP

Details: 30 mM HEPES pH 7.4, 200 mM NaCl, 2 mM TCEP
GridModel: Quantifoil R0.6/1 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY ARRAY
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 283.15 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 11967 / Average exposure time: 2.52 sec. / Average electron dose: 53.685 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 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

DetailsMotion corrected as implemented in cryosparc live
Particle selectionNumber selected: 5417264
CTF correctionSoftware - Name: cryoSPARC (ver. 4.6.2) / Details: performed as in cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: Ab initio
Final reconstructionNumber classes used: 2 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.7.1) / Number images used: 66613
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.7.1)
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC (ver. 4.7.1)
FSC plot (resolution estimation)

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