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- EMDB-71833: Cryo-EM structure of the DCAF11 E3 ligase bound to the DDX18 heli... -

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Basic information

Entry
Database: EMDB / ID: EMD-71833
TitleCryo-EM structure of the DCAF11 E3 ligase bound to the DDX18 helicase mediated by GSH-M12 (DDX18 local refinement)
Map dataMain map of local refinement
Sample
  • Complex: Ternary complex of the E3 ligase DCAF11 and the helicase DDX18 mediated by GSH-M12
    • Protein or peptide: DCAF11
    • Protein or peptide: DDX18
    • Protein or peptide: DDB1
Keywordsglutathionylation / degradation / E3 ligase / helicase / LIGASE
Function / homology
Function and homology information


positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cytokinesis / regulation of mitotic cell cycle phase transition / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / WD40-repeat domain binding ...positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cytokinesis / regulation of mitotic cell cycle phase transition / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / WD40-repeat domain binding / regulation of cell cycle phase transition / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / Cul4A-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / regulation of cellular response to stress / viral release from host cell / cullin family protein binding / regulation of DNA-templated DNA replication initiation / positive regulation of viral genome replication / positive regulation of gluconeogenesis / rhythmic process / regulation of embryonic development / replication fork processing / cellular response to estradiol stimulus / maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / proteasomal protein catabolic process / epigenetic regulation of gene expression / nucleotide-excision repair / regulation of autophagy / Recognition of DNA damage by PCNA-containing replication complex / regulation of circadian rhythm / DNA Damage Recognition in GG-NER / cell population proliferation / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Formation of Incision Complex in GG-NER / cellular response to UV / positive regulation of protein catabolic process / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / regulation of cell population proliferation / site of double-strand break / Neddylation / spermatogenesis / ubiquitin-dependent protein catabolic process / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of apoptotic process / chromosome, telomeric region / RNA helicase activity / protein-macromolecule adaptor activity / protein ubiquitination / RNA helicase / chromosome / DNA repair / DNA damage response / nucleolus / protein-containing complex binding / : / ATP hydrolysis activity / protein-containing complex / DNA binding / RNA binding / extracellular exosome / nucleoplasm / ATP binding / membrane / nucleus / cytoplasm
Similarity search - Function
WD repeat protein DCAF11/LEC14B / : / DDX18/Has1, DEAD-box helicase domain / Domain of unknown function DUF4217 / ATP-dependent rRNA helicase SPB4-like, C-terminal extension / DUF4217 / DEAD-box subfamily ATP-dependent helicases signature. / ATP-dependent RNA helicase DEAD-box, conserved site / DEAD-box RNA helicase Q motif profile. / : ...WD repeat protein DCAF11/LEC14B / : / DDX18/Has1, DEAD-box helicase domain / Domain of unknown function DUF4217 / ATP-dependent rRNA helicase SPB4-like, C-terminal extension / DUF4217 / DEAD-box subfamily ATP-dependent helicases signature. / ATP-dependent RNA helicase DEAD-box, conserved site / DEAD-box RNA helicase Q motif profile. / : / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / DEAD/DEAH box helicase domain / DEAD/DEAH box helicase / Helicase conserved C-terminal domain / helicase superfamily c-terminal domain / WD domain, G-beta repeat / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / G-protein beta WD-40 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
DNA damage-binding protein 1 / DDB1- and CUL4-associated factor 11 / ATP-dependent RNA helicase DDX18
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.38 Å
AuthorsWachter F / Jin CY / Yoon H / Ebert BL / Fischer ES
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1 K99GM154065-01A1 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA214608-09 United States
CitationJournal: Nature / Year: 2026
Title: DCAF11-dependent molecular glue degrader activated by glutathionylation.
Authors: Hojong Yoon / Franziska Wachter / Katharine A Barrett / Cyrus Jin / Anna Rodríguez-Pöhnlein / Justine C Rutter / Ryan J Lumpkin / Rebecca J Metivier / Katherine A Donovan / Kheewoong Baek ...Authors: Hojong Yoon / Franziska Wachter / Katharine A Barrett / Cyrus Jin / Anna Rodríguez-Pöhnlein / Justine C Rutter / Ryan J Lumpkin / Rebecca J Metivier / Katherine A Donovan / Kheewoong Baek / Yongying Jiang / Minwoo Lee / Robert W Kalis / Jianwei Che / Yuan Xiong / Eric S Fischer / Benjamin L Ebert /
Abstract: Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins. ...Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18. Mechanistically, M12 functions as a prodrug that is activated through glutathione S-transferase-mediated glutathionylation. The glutathione moiety binds to an evolutionary conserved glutathione-binding site on DCAF11, and the exposed M12 moiety facilitates neo-substrate recruitment. We demonstrate that this glutathione-dependent mechanism readily enables targeted degradation of a range of proteins. Collectively, these findings establish that metabolically activated compounds can redirect E3 ligase function, thereby expanding the scope of targeted protein degradation and chemically induced proximity.
History
DepositionJul 27, 2025-
Header (metadata) releaseJul 1, 2026-
Map releaseJul 1, 2026-
UpdateAug 26, 2026-
Current statusAug 26, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71833.png

Downloads & links

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Map

FileDownload / File: emd_71833.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMain map of local refinement
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 384 pix.
= 280.32 Å		0.73 Å/pix.
x 384 pix.
= 280.32 Å		0.73 Å/pix.
x 384 pix.
= 280.32 Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.11295511 - 0.21970193
Average (Standard dev.)0.000005746838 (±0.0034310583)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 280.32 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_71833_msk_1.map
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Mask #2

Fileemd_71833_msk_2.map
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Additional map: Sharpened map of local refinement

Fileemd_71833_additional_1.map
AnnotationSharpened map of local refinement
Projections & Slices
AxesZYX

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Half map: Half map 2

Fileemd_71833_half_map_1.map
AnnotationHalf map 2
Projections & Slices
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Half map: Half map 1

Fileemd_71833_half_map_2.map
AnnotationHalf map 1
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Sample components

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Entire : Ternary complex of the E3 ligase DCAF11 and the helicase DDX18 me...

EntireName: Ternary complex of the E3 ligase DCAF11 and the helicase DDX18 mediated by GSH-M12
Components
  • Complex: Ternary complex of the E3 ligase DCAF11 and the helicase DDX18 mediated by GSH-M12
    • Protein or peptide: DCAF11
    • Protein or peptide: DDX18
    • Protein or peptide: DDB1

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Supramolecule #1: Ternary complex of the E3 ligase DCAF11 and the helicase DDX18 me...

SupramoleculeName: Ternary complex of the E3 ligase DCAF11 and the helicase DDX18 mediated by GSH-M12
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: DCAF11

MacromoleculeName: DCAF11 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MDWSHPQFEK SAVGLNDIFE AQKIEWHEGG GGSGENLYFQ GGGRMGSRNS SSAGSGSGDP SEGLPRRGAG LRRSEEEEEE DEDVDLAQV LAYLLRRGQV RLVQGGGAAN LQFIQALLDS EEENDRAWDG RLGDRYNPPV DATPDTRELE FNEIKTQVEL A TGQLGLRR ...String:
MDWSHPQFEK SAVGLNDIFE AQKIEWHEGG GGSGENLYFQ GGGRMGSRNS SSAGSGSGDP SEGLPRRGAG LRRSEEEEEE DEDVDLAQV LAYLLRRGQV RLVQGGGAAN LQFIQALLDS EEENDRAWDG RLGDRYNPPV DATPDTRELE FNEIKTQVEL A TGQLGLRR AAQKHSFPRM LHQRERGLCH RGSFSLGEQS RVISHFLPND LGFTDSYSQK AFCGIYSKDG QIFMSACQDQ TI RLYDCRY GRFRKFKSIK ARDVGWSVLD VAFTPDGNHF LYSSWSDYIH ICNIYGEGDT HTALDLRPDE RRFAVFSIAV SSD GREVLG GANDGCLYVF DREQNRRTLQ IESHEDDVNA VAFADISSQI LFSGGDDAIC KVWDRRTMRE DDPKPVGALA GHQD GITFI DSKGDARYLI SNSKDQTIKL WDIRRFSSRE GMEASRQAAT QQNWDYRWQQ VPKKAWRKLK LPGDSSLMTY RGHGV LHTL IRCRFSPIHS TGQQFIYSGC STGKVVVYDL LSGHIVKKLT NHKACVRDVS WHPFEEKIVS SSWDGNLRLW QYRQAE YFQ DDMPESEECA SAPAPVPQSS TPFSSPQ

UniProtKB: DDB1- and CUL4-associated factor 11

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Macromolecule #2: DDX18

MacromoleculeName: DDX18 / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MDYKDDDDKS AVDENLYFQG GGRTGAFEDT SFASLCNLVN ENTLKAIKEM GFTNMTEIQH KSIRPLLEGR DLLAAAKTGS GKTLAFLIP AVELIVKLRF MPRNGTGVLI LSPTRELAMQ TFGVLKELMT HHVHTYGLIM GGSNRSAEAQ KLGNGINIIV A TPGRLLDH ...String:
MDYKDDDDKS AVDENLYFQG GGRTGAFEDT SFASLCNLVN ENTLKAIKEM GFTNMTEIQH KSIRPLLEGR DLLAAAKTGS GKTLAFLIP AVELIVKLRF MPRNGTGVLI LSPTRELAMQ TFGVLKELMT HHVHTYGLIM GGSNRSAEAQ KLGNGINIIV A TPGRLLDH MQNTPGFMYK NLQCLVIDEA DRILDVGFEE ELKQIIKLLP TRRQTMLFSA TQTRKVEDLA RISLKKEPLY VG VDDDKAN ATVDGLEQGY VVCPSEKRFL LLFTFLKKNR KKKLMVFFSS CMSVKYHYEL LNYIDLPVLA IHGKQKQNKR TTT FFQFCN ADSGTLLCTD VAARGLDIPE VDWIVQYDPP DDPKEYIHRV GRTARGLNGR GHALLILRPE ELGFLRYLKQ SKVP LSEFD FSWSKISDIQ SQLEKLIEKN YFLHKSAQEA YKSYIRAYDS HSLKQIFNVN NLNLPQVALS FGFKVPPFVD LNV

UniProtKB: ATP-dependent RNA helicase DDX18

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Macromolecule #3: DDB1

MacromoleculeName: DDB1 / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGSSHHHHHH SAAHIVMVDA YKPTKGGRMS YNYVVTAQKP TAVNGCVTGH FTSAEDLNLL IAKNTRLEIY VVTAEGLRPV KEVGMYGKIA VMELFRPKGE SKDLLFILTA KYNACILEYK QSGESIDIIT RAHGNVQDRI GRPSETGIIG IIDPECRMIG LRLYDGLFKV ...String:
MGSSHHHHHH SAAHIVMVDA YKPTKGGRMS YNYVVTAQKP TAVNGCVTGH FTSAEDLNLL IAKNTRLEIY VVTAEGLRPV KEVGMYGKIA VMELFRPKGE SKDLLFILTA KYNACILEYK QSGESIDIIT RAHGNVQDRI GRPSETGIIG IIDPECRMIG LRLYDGLFKV IPLDRDNKEL KAFNIRLEEL HVIDVKFLYG CQAPTICFVY QDPQGRHVKT YEVSLREKEF NKGPWKQENV EAEASMVIAV PEPFGGAIII GQESITYHNG DKYLAIAPPI IKQSTIVCHN RVDPNGSRYL LGDMEGRLFM LLLEKEEQMD GTVTLKDLRV ELLGETSIAE CLTYLDNGVV FVGSRLGDSQ LVKLNVDSNE QGSYVVAMET FTNLGPIVDM CVVDLERQGQ GQLVTCSGAF KEGSLRIIRN GIGGNGNSGE IQKLHIRTVP LYESPRKICY QEVSQCFGVL SSRIEVQDTS GGTTALRPSA STQALSSSVS SSKLFSSSTA PHETSFGEEV EVHNLLIIDQ HTFEVLHAHQ FLQNEYALSL VSCKLGKDPN TYFIVGTAMV YPEEAEPKQG RIVVFQYSDG KLQTVAEKEV KGAVYSMVEF NGKLLASINS TVRLYEWTTE KELRTECNHY NNIMALYLKT KGDFILVGDL MRSVLLLAYK PMEGNFEEIA RDFNPNWMSA VEILDDDNFL GAENAFNLFV CQKDSAATTD EERQHLQEVG LFHLGEFVNV FCHGSLVMQN LGETSTPTQG SVLFGTVNGM IGLVTSLSES WYNLLLDMQN RLNKVIKSVG KIEHSFWRSF HTERKTEPAT GFIDGDLIES FLDISRPKMQ EVVANLQYDD GSGMKREATA DDLIKVVEEL TRIH

UniProtKB: DNA damage-binding protein 1

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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

Concentration0.5 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
50.0 mMC8H18N2O4SHEPES
200.0 mMNaClsodium chloride
5.0 mMC9H15O6PTCEP

Details: 50mM HEPES pH 7.4 200mM NaCl 5 mM TCEP
GridModel: Quantifoil R0.6/1 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / 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
SoftwareName: EPU
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 10632 / Average exposure time: 3.16 sec. / Average electron dose: 52.004 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: 0.6 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 on the fly as implemented in cryosparc live
Particle selectionNumber selected: 3767503 / Details: Topaz
CTF correctionSoftware - Name: cryoSPARC (ver. 4.5.3) / Details: As implemented in cryosparc live / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab initio
Final reconstructionNumber classes used: 2 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.38 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.2) / Details: As in Cryosparc / Number images used: 136583
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5.3)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5.3)
Final 3D classificationNumber classes: 12 / Software - Name: cryoSPARC (ver. 4.5.3)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

1-v4

chain_id: A, source_name: AlphaFold, initial_model_type: in silico model

5fqd

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

1-v4

chain_id: A, source_name: AlphaFold, initial_model_type: in silico model
RefinementSpace: REAL / Protocol: OTHER / Target criteria: real space correlation

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