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- PDB-9c5v: Cryo EM structure of a DCAF2:degrader:BRD4 ternary complex -

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Basic information

Entry
Database: PDB / ID: 9c5v
TitleCryo EM structure of a DCAF2:degrader:BRD4 ternary complex
Components
  • Bromodomain-containing protein 4
  • DET1- and DDB1-associated protein 1
  • DNA damage-binding protein 1
  • Denticleless protein homolog
KeywordsLIGASE / DTL / DDB1 / DDA1 / BRD4 / degrader / covalent
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 cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex ...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 cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / mitotic G2 DNA damage checkpoint signaling / negative regulation of reproductive process / negative regulation of developmental process / RNA polymerase II C-terminal domain binding / cullin family protein binding / P-TEFb complex binding / viral release from host cell / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / protein monoubiquitination / positive regulation of G2/M transition of mitotic cell cycle / ectopic germ cell programmed cell death / translesion synthesis / positive regulation of T-helper 17 cell lineage commitment / positive regulation of viral genome replication / proteasomal protein catabolic process / response to UV / : / positive regulation of gluconeogenesis / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / transcription coregulator activity / nucleotide-excision repair / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / positive regulation of transcription elongation by RNA polymerase II / Formation of TC-NER Pre-Incision Complex / Formation of Incision Complex in GG-NER / regulation of circadian rhythm / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Wnt signaling pathway / protein polyubiquitination / positive regulation of protein catabolic process / cellular response to UV / p53 binding / rhythmic process / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / site of double-strand break / Neddylation / chromosome / regulation of inflammatory response / ubiquitin-dependent protein catabolic process / histone binding / protein-macromolecule adaptor activity / nuclear membrane / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transcription coactivator activity / chromosome, telomeric region / DNA replication / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / protein ubiquitination / regulation of cell cycle / chromatin remodeling / DNA repair / protein serine/threonine kinase activity / apoptotic process / DNA damage response / centrosome / chromatin binding / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / chromatin / positive regulation of DNA-templated transcription / protein-containing complex binding / nucleolus / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / extracellular space / DNA binding / extracellular exosome / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
: / DET1- and DDB1-associated protein 1, N-terminal / DET1- and DDB1-associated protein 1 / Det1 complexing ubiquitin ligase / 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 ...: / DET1- and DDB1-associated protein 1, N-terminal / DET1- and DDB1-associated protein 1 / Det1 complexing ubiquitin ligase / 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 / 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 / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / 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 / DNA damage-binding protein 1 / DET1- and DDB1-associated protein 1 / Denticleless protein homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsMcMahon, E.J. / Wang, W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Structure / Year: 2025
Title: Structural Basis for DCAF2 as a Novel E3 Ligase for PROTAC-Mediated Targeted Protein Degradation
Authors: McMahon, E.J. / Cioffi, A.G. / Visperas, P.R. / Lin, Y. / Shaghafi, M. / Daczkowski, C.M. / Hermann, J.C. / Everley, R.A. / Neve, R.M. / Erlanson, D.A. / Webster, K.R. / Narayan, V. / Wang, W.
History
DepositionJun 6, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 1, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Denticleless protein homolog
B: DNA damage-binding protein 1
D: Bromodomain-containing protein 4
C: DET1- and DDB1-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)207,2895
Polymers206,4094
Non-polymers8801
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Denticleless protein homolog / DDB1- and CUL4-associated factor 2 / Lethal(2) denticleless protein homolog / Retinoic acid- ...DDB1- and CUL4-associated factor 2 / Lethal(2) denticleless protein homolog / Retinoic acid-regulated nuclear matrix-associated protein


Mass: 51887.121 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DTL, CDT2, CDW1, DCAF2, L2DTL, RAMP / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9NZJ0
#2: Protein DNA damage-binding protein 1 / DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / ...DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / HBV X-associated protein 1 / XAP-1 / UV-damaged DNA-binding factor / UV-damaged DNA-binding protein 1 / UV-DDB 1 / XPE-binding factor / XPE-BF / Xeroderma pigmentosum group E-complementing protein / XPCe


Mass: 127097.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#3: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 15568.838 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#4: Protein DET1- and DDB1-associated protein 1 / Placenta cross-immune reaction antigen 1 / PCIA-1


Mass: 11855.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDA1, C19orf58, PCIA1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BW61
#5: Chemical ChemComp-A1AUO / N-({4-[(4-{[1'-(chloroacetyl)-3'-oxo-3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-quinoxalin]-6'-yl]oxy}piperidin-1-yl)methyl]phenyl}methyl)-2-[(6S,10P)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]acetamide


Mass: 879.896 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C46H48Cl2N8O4S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: DCAF2:degrader:BRD4 ternary complex / Type: COMPLEX / Entity ID: #1-#2, #4, #3 / Source: RECOMBINANT
Molecular weightValue: 0.206 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 1.4 sec. / Electron dose: 50.21 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1
EM imaging opticsPhase plate: VOLTA PHASE PLATE

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2Leginonimage acquisition
4cryoSPARCCTF correction
7Cootmodel fitting
9PHENIX1.20.1_4487:model refinement
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1277208
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 70550 / Symmetry type: POINT
RefinementHighest resolution: 3.36 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00413241
ELECTRON MICROSCOPYf_angle_d0.83217946
ELECTRON MICROSCOPYf_dihedral_angle_d11.3591815
ELECTRON MICROSCOPYf_chiral_restr0.0472009
ELECTRON MICROSCOPYf_plane_restr0.0052307

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