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- EMDB-54215: Ternary complex of an improved charged molecular glue degrader ZZ... -

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Basic information

Entry
Database: EMDB / ID: EMD-54215
TitleTernary complex of an improved charged molecular glue degrader ZZ2-SO2H, BRD4(BD1) neosubstrate, and the CTLH E3 ligase receptor module YPEL5-WDR26
Map data
Sample
  • Complex: ZZ2-SO2H-induced complex between YPEL5-CTLH E3 ligase and the first bromodomain (BD1) of BRD4
    • Protein or peptide: WD repeat-containing protein 26
    • Protein or peptide: Protein yippee-like 5
    • Protein or peptide: Bromodomain-containing protein 4
  • Ligand: ZINC ION
  • Ligand: 2,6-bis(chloranyl)-4-[[4-[(9S)-4,5,13-trimethyl-9-[2-[(2-methylpropan-2-yl)oxy]-2-oxidanylidene-ethyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]carbamoyl]benzenesulfinic acid
  • Ligand: water
KeywordsE3 ubiquitin ligase / CTLH / GID / YPEL5 / Molecular Glue Degrader / Targeted Protein Degradation / LIGASE
Function / homology
Function and homology information


GID complex / mitotic spindle pole / histone H4K8ac reader activity / RNA polymerase II C-terminal domain binding / histone H3K27ac reader activity / P-TEFb complex binding / histone H3K9ac reader activity / negative regulation of DNA damage checkpoint / histone H4 reader activity / histone H4K5ac reader activity ...GID complex / mitotic spindle pole / histone H4K8ac reader activity / RNA polymerase II C-terminal domain binding / histone H3K27ac reader activity / P-TEFb complex binding / histone H3K9ac reader activity / negative regulation of DNA damage checkpoint / histone H4 reader activity / histone H4K5ac reader activity / histone H4K12ac reader activity / host-mediated suppression of viral transcription / histone H4K16ac reader activity / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / ubiquitin ligase complex / RNA polymerase II CTD heptapeptide repeat kinase activity / Regulation of pyruvate metabolism / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / tertiary granule lumen / chromosome / regulation of inflammatory response / midbody / histone binding / Potential therapeutics for SARS / ficolin-1-rich granule lumen / proteasome-mediated ubiquitin-dependent protein catabolic process / positive regulation of canonical NF-kappaB signal transduction / transcription coactivator activity / cell population proliferation / transcription cis-regulatory region binding / chromatin remodeling / protein serine/threonine kinase activity / DNA damage response / Neutrophil degranulation / chromatin binding / regulation of transcription by RNA polymerase II / centrosome / positive regulation of DNA-templated transcription / chromatin / enzyme binding / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular region / nucleoplasm / metal ion binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Yippee domain / Yippee family / Yippee domain profile. / : / : / LisH-like dimerisation domain / C-terminal to LisH motif. / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / Yippee/Mis18/Cereblon ...Yippee domain / Yippee family / Yippee domain profile. / : / : / LisH-like dimerisation domain / C-terminal to LisH motif. / CTLH, C-terminal LisH motif / C-terminal to LisH (CTLH) motif profile. / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / LIS1 homology (LisH) motif profile. / LIS1 homology motif / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Bromodomain-containing protein 4 / Protein yippee-like 5 / WD repeat-containing protein 26
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.42 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: To Be Published
Title: Molecular Glue Prodrug Discovery Enabled by Targeted Degron Display
Authors: Zhuang Z / Woong Sub B / Chrustowicz J / Kozicka Z / Hinshaw SM / Li VL / Donovan KA / Sepic S / You I / Slabicki M / Fischer ES / Ebert BL / Schulman BA / Gray NS
History
DepositionJul 1, 2025-
Header (metadata) releaseApr 8, 2026-
Map releaseApr 8, 2026-
UpdateApr 8, 2026-
Current statusApr 8, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54215.png

Downloads & links

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Map

FileDownload / File: emd_54215.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.27 Å/pix.
x 224 pix.
= 283.808 Å		1.27 Å/pix.
x 224 pix.
= 283.808 Å		1.27 Å/pix.
x 224 pix.
= 283.808 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.267 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0387
Minimum - Maximum-0.13395937 - 0.25237688
Average (Standard dev.)0.00018563932 (±0.0045567947)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 283.80798 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_54215_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Map sharpened with DeepEMhancer.

Fileemd_54215_additional_1.map
AnnotationMap sharpened with DeepEMhancer.
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_54215_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_54215_half_map_2.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : ZZ2-SO2H-induced complex between YPEL5-CTLH E3 ligase and the fir...

EntireName: ZZ2-SO2H-induced complex between YPEL5-CTLH E3 ligase and the first bromodomain (BD1) of BRD4
Components
  • Complex: ZZ2-SO2H-induced complex between YPEL5-CTLH E3 ligase and the first bromodomain (BD1) of BRD4
    • Protein or peptide: WD repeat-containing protein 26
    • Protein or peptide: Protein yippee-like 5
    • Protein or peptide: Bromodomain-containing protein 4
  • Ligand: ZINC ION
  • Ligand: 2,6-bis(chloranyl)-4-[[4-[(9S)-4,5,13-trimethyl-9-[2-[(2-methylpropan-2-yl)oxy]-2-oxidanylidene-ethyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]carbamoyl]benzenesulfinic acid
  • Ligand: water

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Supramolecule #1: ZZ2-SO2H-induced complex between YPEL5-CTLH E3 ligase and the fir...

SupramoleculeName: ZZ2-SO2H-induced complex between 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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Macromolecule #1: WD repeat-containing protein 26

MacromoleculeName: WD repeat-containing protein 26 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.539773 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MQANGAGGGG GGGGGGGGGG GGGGGQGQTP ELACLSAQNG ESSPSSSSSA GDLAHANGLL PSAPSAASNN SNSLNVNNGV PGGAAAASS ATVAAASATT AASSSLATPE LGSSLKKKKR LSQSDEDVIR LIGQHLNGLG LNQTVDLLMQ ESGCRLEHPS A TKFRNHVM ...String:
MQANGAGGGG GGGGGGGGGG GGGGGQGQTP ELACLSAQNG ESSPSSSSSA GDLAHANGLL PSAPSAASNN SNSLNVNNGV PGGAAAASS ATVAAASATT AASSSLATPE LGSSLKKKKR LSQSDEDVIR LIGQHLNGLG LNQTVDLLMQ ESGCRLEHPS A TKFRNHVM EGDWDKAEND LNELKPLVHS PHAIVRMKFL LLQQKYLEYL EDGKVLEALQ VLRCELTPLK YNTERIHVLS GY LMCSHAE DLRAKAEWEG KGTASRSKLL DKLQTYLPPS VMLPPRRLQT LLRQAVELQR DRCLYHNTKL DNNLDSVSLL IDH VCSRRQ FPCYTQQILT EHCNEVWFCK FSNDGTKLAT GSKDTTVIIW QVDPDTHLLK LLKTLEGHAY GVSYIAWSPD DNYL VACGP DDCSELWLWN VQTGELRTKM SQSHEDSLTS VAWNPDGKRF VTGGQRGQFY QCDLDGNLLD SWEGVRVQCL WCLSD GKTV LASDTHQRIR GYNFEDLTDR NIVQEDHPIM SFTISKNGRL ALLNVATQGV HLWDLQDRVL VRKYQGVTQG FYTIHS CFG GHNEDFIASG SEDHKVYIWH KRSELPIAEL TGHTRTVNCV SWNPQIPSMM ASASDDGTVR IWGPAPFIDH QNIEEEC SS MDS

UniProtKB: WD repeat-containing protein 26

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Macromolecule #2: Protein yippee-like 5

MacromoleculeName: Protein yippee-like 5 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.860658 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MGRIFLDHIG GTRLFSCANC DTILTNRSEL ISTRFTGATG RAFLFNKVVN LQYSEVQDRV MLTGRHMVRD VSCKNCNSKL GWIYEFATE DSQRYKEGRV ILERALVRES EGFEEHVPSD NS

UniProtKB: Protein yippee-like 5

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Macromolecule #3: Bromodomain-containing protein 4

MacromoleculeName: Bromodomain-containing protein 4 / type: protein_or_peptide / ID: 3
Details: The first bromodomain (BD1) of BRD4. The GGSGS sequence is a linker between BD1 and the upstream TEV cleavage site.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.226416 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GGSGSNPPPP ETSNPNKPKR QTNQLQYLLR VVLKTLWKHQ FAWPFQQPVD AVKLNLPDYY KIIKTPMDMG TIKKRLENNY YWNAQECIQ DFNTMFTNCY IYNKPGDDIV LMAEALEKLF LQKINELPTE E

UniProtKB: Bromodomain-containing protein 4

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 3 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: 2,6-bis(chloranyl)-4-[[4-[(9S)-4,5,13-trimethyl-9-[2-[(2-methylpr...

MacromoleculeName: 2,6-bis(chloranyl)-4-[[4-[(9S)-4,5,13-trimethyl-9-[2-[(2-methylpropan-2-yl)oxy]-2-oxidanylidene-ethyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl] ...Name: 2,6-bis(chloranyl)-4-[[4-[(9S)-4,5,13-trimethyl-9-[2-[(2-methylpropan-2-yl)oxy]-2-oxidanylidene-ethyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]carbamoyl]benzenesulfinic acid
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1IL8
Molecular weightTheoretical: 674.618 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 63.6 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: 5422892
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

18170

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 24545
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9ghq
PDB Unreleased entry


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-9rsc:
Ternary complex of an improved charged molecular glue degrader ZZ2-SO2H, BRD4(BD1) neosubstrate, and the CTLH E3 ligase receptor module YPEL5-WDR26

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