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- PDB-9sai: Ternary PROTAC-mediated complex consisting of Cereblon, DDB1 and ... -

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Basic information

Entry
Database: PDB / ID: 9sai
TitleTernary PROTAC-mediated complex consisting of Cereblon, DDB1 and BRD4-BD1, non-covalently linked by JQ1-AcN
Components
  • Bromodomain-containing protein 4
  • DNA damage-binding protein 1
  • Protein cereblon
KeywordsLIGASE / ternary complex / PROTAC / cereblon
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / 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 ...negative regulation of monoatomic ion transmembrane transport / 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 / histone H4K8ac reader activity / locomotory exploration behavior / regulation of cell cycle phase transition / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / Cul4B-RING E3 ubiquitin ligase complex / RNA polymerase II C-terminal domain binding / histone H3K27ac reader activity / negative regulation of DNA damage checkpoint / P-TEFb complex binding / histone H3K9ac reader activity / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / histone H4 reader activity / regulation of cellular response to stress / histone H4K5ac reader activity / histone H4K12ac reader activity / limb development / host-mediated suppression of viral transcription / histone H4K16ac reader activity / viral release from host cell / cullin family protein binding / positive regulation of T-helper 17 cell lineage commitment / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / regulation of DNA-templated DNA replication initiation / positive regulation of viral genome replication / positive regulation of gluconeogenesis / positive regulation of G2/M transition of mitotic cell cycle / RNA polymerase II CTD heptapeptide repeat kinase activity / regulation of embryonic development / replication fork processing / condensed nuclear chromosome / proteasomal protein catabolic process / positive regulation of transcription elongation by RNA polymerase II / epigenetic regulation of gene expression / positive regulation of protein-containing complex assembly / nucleotide-excision repair / regulation of autophagy / Recognition of DNA damage by PCNA-containing replication complex / regulation of circadian rhythm / cell population proliferation / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / transcription coregulator activity / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Formation of Incision Complex in GG-NER / positive regulation of protein catabolic process / p53 binding / cellular response to UV / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / rhythmic process / regulation of cell population proliferation / Regulation of PD-L1(CD274) transcription / site of double-strand break / chromosome / regulation of inflammatory response / Neddylation / spermatogenesis / ubiquitin-dependent protein catabolic process / histone binding / Potential therapeutics for SARS / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of apoptotic process / transmembrane transporter binding / positive regulation of canonical NF-kappaB signal transduction / protein-macromolecule adaptor activity / chromosome, telomeric region / transcription coactivator activity / transcription cis-regulatory region binding / protein ubiquitination / chromatin remodeling / DNA repair / protein serine/threonine kinase activity / chromatin binding / regulation of transcription by RNA polymerase II / DNA damage response / nucleolus / positive regulation of DNA-templated transcription / protein-containing complex binding / chromatin / perinuclear region of cytoplasm / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex
Similarity search - Function
Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / : ...Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / : / 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 / PUA-like superfamily / 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 / 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 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.66 Å
AuthorsFischer, G. / Peter, D. / Arce-Solano, S. / Kessler, D.
Funding support1items
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 7, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 29, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Protein cereblon
A: DNA damage-binding protein 1
C: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)159,7955
Polymers159,0063
Non-polymers7892
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Protein cereblon


Mass: 50559.559 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Production host: unidentified baculovirus / References: UniProt: Q96SW2
#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: 93347.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: beta-propeller B removed,beta-propeller B removed,beta-propeller B removed,beta-propeller B removed,beta-propeller B removed,beta-propeller B removed,beta-propeller B removed,beta-propeller B removed
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: unidentified baculovirus / References: UniProt: Q16531
#3: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 15099.380 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: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-A1JM3 / N-[(2S)-1-[[(3S)-2,5-bis(oxidanylidene)pyrrolidin-3-yl]amino]-1-oxidanylidene-propan-2-yl]-9-[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-9-yl]ethanoylamino]nonanamide


Mass: 723.285 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H43ClN8O5S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: Ternary PROTAC-mediated complex consisting of Cereblon, DDB1 and BRD4-BD1, non-covalently linked by JQ1-AcN
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: unidentified baculovirus
Buffer solutionpH: 7.5 / Details: 20 mM HEPES, 100 mM NaCl, 0.25 mM TCEP, pH: 7.5
Buffer component
IDConc.NameBuffer-ID
120 mMHEPES1
2100 mMNaCl1
30.25 mMTCEP1
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: complex purified via size exclusion chromatography
Specimen supportDetails: QF-1.2/1.3-3C AuFoil / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 3 / Num. of real images: 21670
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIX1.21.2_5419model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.66 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 184507 / Symmetry type: POINT
Atomic model buildingB value: 94 / Protocol: FLEXIBLE FIT / Space: REAL
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeChain-IDInitial refinement model-ID
13mxf

3mxf

A3mxfA1
25fqd

5fqd

A5fqdA2
35fqd

5fqd

B5fqdB2
RefinementHighest resolution: 2.66 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00610780
ELECTRON MICROSCOPYf_angle_d0.71914604
ELECTRON MICROSCOPYf_dihedral_angle_d5.2971462
ELECTRON MICROSCOPYf_chiral_restr0.0491636
ELECTRON MICROSCOPYf_plane_restr0.0051891

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