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- PDB-9q2d: Cryo-EM structure of ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1 ... -

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Basic information

Entry
Database: PDB / ID: 9q2d
TitleCryo-EM structure of ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1 (molecular glue degrader)
Components
  • DNA damage-binding protein 1
  • DNA-binding protein Ikaros
  • Protein cereblon
KeywordsLIGASE / Cereblon / degrader / Ikaros / IKZF1 / DDB1 / molecular glue
Function / homology
Function and homology information


lymphocyte differentiation / 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 / NOTCH3 Intracellular Domain Regulates Transcription / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding ...lymphocyte differentiation / 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 / NOTCH3 Intracellular Domain Regulates Transcription / 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 / negative regulation of reproductive process / negative regulation of developmental process / mesoderm development / locomotory exploration behavior / pericentric heterochromatin / cullin family protein binding / viral release from host cell / positive regulation of Wnt signaling pathway / ectopic germ cell programmed cell death / negative regulation of protein-containing complex assembly / positive regulation of viral genome replication / proteasomal protein catabolic process / positive regulation of gluconeogenesis / erythrocyte differentiation / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / nucleotide-excision repair / positive regulation of protein-containing complex assembly / 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 / regulation of circadian rhythm / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Wnt signaling pathway / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / site of double-strand break / Neddylation / chromatin organization / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / chromosome, telomeric region / protein ubiquitination / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / DNA repair / negative regulation of DNA-templated transcription / apoptotic process / DNA damage response / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / protein-containing complex / extracellular space / DNA binding / extracellular exosome / zinc ion binding / nucleoplasm / metal ion binding / identical protein binding / nucleus / membrane / cytosol / cytoplasm
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 / PUA-like superfamily / Zinc finger, C2H2 type / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Chem-85C / DNA-binding protein Ikaros / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.94 Å
AuthorsZhu, J. / Pagarigan, B.E. / Tran, E.T.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J Med Chem / Year: 2025
Title: Application of Weighted Interaction-Fingerprints for Rationalizing Neosubstrate Potency and Selectivity of Cereblon-Based Molecular Glues.
Authors: Guilian Luchini / Shuang Liu / Hannah L Powers / Emily Cherney / Jinyi Zhu / Kristina Danga / Joel W Thompson / Lihong Shi / Barbra Pagarigan / Dong Donna Wei / Peter Park / Andrew P Degnan ...Authors: Guilian Luchini / Shuang Liu / Hannah L Powers / Emily Cherney / Jinyi Zhu / Kristina Danga / Joel W Thompson / Lihong Shi / Barbra Pagarigan / Dong Donna Wei / Peter Park / Andrew P Degnan / Christoph W Zapf / Jennifer R Riggs / Scott Johnson / Thomas Cummins /
Abstract: Cullin-RING Ligase 4 Cereblon (CRL4) (CRBN) E3 ligase modulatory drugs (CELMoDs) make up a successful class of compounds targeting neosubstrates for proteasome-dependent degradation. Early ...Cullin-RING Ligase 4 Cereblon (CRL4) (CRBN) E3 ligase modulatory drugs (CELMoDs) make up a successful class of compounds targeting neosubstrates for proteasome-dependent degradation. Early immunomodulatory drugs (IMiDs) target Ikaros and Aiolos degradation. In addition, there are ongoing clinical trials targeting the degradation of biologically relevant proteins such as GSPT1, CK1α, and Helios with CRBN-based molecular glues. To date, most advanced preclinical and clinical CRBN-based molecular glues recruit their neosubstrates through canonical G-motifs, secondary protein features that are structurally similar but have significantly different amino acid sequence identities. Analogous to the development of kinase inhibitors, optimizing both neosubstrate recruitment and degradation selectivity is important to minimize potential off-target activity. Here, we describe a computational structure-based approach to analyze and predict putative ligand interactions important in the neosubstrate ternary complex. This approach provides valuable insights for enhanced designs toward the development of more selective and efficacious CRBN-based molecular glues.
History
DepositionAug 15, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 1, 2025Provider: repository / Type: Initial release
Remark 650HELIX DETERMINATION METHOD: MOE
Remark 700SHEET DETERMINATION METHOD: MOE

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)157,2326
Polymers156,6603
Non-polymers5723
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 DNA-binding protein Ikaros / Ikaros family zinc finger protein 1 / Lymphoid transcription factor LyF-1


Mass: 9731.428 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IKZF1, IK1, IKAROS, LYF1, ZNFN1A1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q13422
#2: Protein Protein cereblon


Mass: 53581.984 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Cell (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2
#3: 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 / Fragment: UNP residues 1-395,706-1140
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Cell (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-85C / 1-(3-chloro-4-methylphenyl)-3-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea


Mass: 440.880 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21ClN4O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN
Nonpolymer detailsLIG DICTIONARY 52 55 Other LIG C1 C1 C 0 YNN 1 LIG C10 C10 C 0 YNN 2 LIG C11 C11 C 0 YNN 3 LIG C12 ...LIG DICTIONARY 52 55 Other LIG C1 C1 C 0 YNN 1 LIG C10 C10 C 0 YNN 2 LIG C11 C11 C 0 YNN 3 LIG C12 C12 C 0 YNN 4 LIG C13 C13 C 0 NNN 5 LIG C14 C14 C 0 NNN 6 LIG C15 C15 C 0 NNN 7 LIG C16 C16 C 0 NNN 8 LIG C17 C17 C 0 NNN 9 LIG C18 C18 C 0 NNN 10 LIG C19 C19 C 0 NNN 11 LIG C2 C2 C 0 YNN 12 LIG C20 C20 C 0 NNS 13 LIG C21 C21 C 0 NNN 14 LIG C22 C22 C 0 NNN 15 LIG C3 C3 C 0 YNN 16 LIG C4 C4 C 0 YNN 17 LIG C5 C5 C 0 YNN 18 LIG C6 C6 C 0 YNN 19 LIG C7 C7 C 0 YNN 20 LIG C8 C8 C 0 YNN 21 LIG C9 C9 C 0 YNN 22 LIG N1 N1 N 0 NNN 23 LIG N2 N2 N 0 NNN 24 LIG N3 N3 N 0 NNN 25 LIG N4 N4 N 0 NNN 26 LIG O1 O1 O 0 NNN 27 LIG O2 O2 O 0 NNN 28 LIG O3 O3 O 0 NNN 29 LIG O4 O4 O 0 NNN 30 LIG CL1 CL1 Cl 0 NNN 31 LIG H1 H1 H 0 NNN 32 LIG H2 H2 H 0 NNN 33 LIG H3 H3 H 0 NNN 34 LIG H10 H10 H 0 NNN 35 LIG H11 H11 H 0 NNN 36 LIG H12 H12 H 0 NNN 37 LIG H13 H13 H 0 NNN 38 LIG H14 H14 H 0 NNN 39 LIG H15 H15 H 0 NNN 40 LIG H16 H16 H 0 NNN 41 LIG H17 H17 H 0 NNN 42 LIG H18 H18 H 0 NNN 43 LIG H19 H19 H 0 NNN 44 LIG H20 H20 H 0 NNN 45 LIG H21 H21 H 0 NNN 46 LIG H4 H4 H 0 NNN 47 LIG H5 H5 H 0 NNN 48 LIG H6 H6 H 0 NNN 49 LIG H7 H7 H 0 NNN 50 LIG H8 H8 H 0 NNN 51 LIG H9 H9 H 0 NNN 52 LIG C1 C2 SING YN 1 LIG C1 C7 DOUB YN 2 LIG C1 H1 SING NN 3 LIG C10 C12 SING YN 4 LIG C10 C21 SING NN 5 LIG C10 C3 DOUB YN 6 LIG C11 C4 DOUB YN 7 LIG C11 C6 SING YN 8 LIG C11 N3 SING NN 9 LIG C12 C6 DOUB YN 10 LIG C12 CL1 SING NN 11 LIG C13 C7 SING NN 12 LIG C13 N2 SING NN 13 LIG C13 O1 DOUB NN 14 LIG C14 C18 SING NN 15 LIG C14 N1 SING NN 16 LIG C14 O2 DOUB NN 17 LIG C15 C20 SING NN 18 LIG C15 N1 SING NN 19 LIG C15 O3 DOUB NN 20 LIG C16 N3 SING NN 21 LIG C16 N4 SING NN 22 LIG C16 O4 DOUB NN 23 LIG C17 C8 SING NN 24 LIG C17 N2 SING NN 25 LIG C17 H7 SING NN 26 LIG C17 H8 SING NN 27 LIG C18 C19 SING NN 28 LIG C18 H10 SING NN 29 LIG C18 H9 SING NN 30 LIG C19 C20 SING NN 31 LIG C19 H11 SING NN 32 LIG C19 H12 SING NN 33 LIG C2 C9 DOUB YN 34 LIG C2 H2 SING NN 35 LIG C20 N2 SING NN 36 LIG C20 H13 SING NN 37 LIG C21 H14 SING NN 38 LIG C21 H15 SING NN 39 LIG C21 H16 SING NN 40 LIG C22 C9 SING NN 41 LIG C22 N4 SING NN 42 LIG C22 H17 SING NN 43 LIG C22 H18 SING NN 44 LIG C3 C4 SING YN 45 LIG C3 H3 SING NN 46 LIG C4 H4 SING NN 47 LIG C5 C8 DOUB YN 48 LIG C5 C9 SING YN 49 LIG C5 H5 SING NN 50 LIG C6 H6 SING NN 51 LIG C7 C8 SING YN 52 LIG N1 H19 SING NN 53 LIG N3 H20 SING NN 54 LIG N4 H21 SING NN 55 ZN DICTIONARY 1 0 Other ZN ZN ZN Zn 2 NNN 1

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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 complex Ikaros-ZF2:CC-885:CRBN:DDB1 / Type: COMPLEX / Details: ternary complex of three proteins and CC-885 / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.15 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7
Buffer component
IDConc.NameFormulaBuffer-ID
110 mM(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethanesulfonic acid)1
2240 mMsodium chlorideNaCl1
33 mMtris(2-carboxyethyl)phosphine1
40.3 %Dimethyl sulfoxide1
50.001 %Lauryl Maltose Neopentyl Glycol1
SpecimenConc.: 3.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 278 K / Details: blot time 4 sec blot force 4

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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: 75000 X / Nominal defocus max: 1600 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.2 sec. / Electron dose: 29.1 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 9754

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
7Cootmodel fitting
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 20365602
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 84299 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 8D81

8d81


Accession code: 8D81 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.94 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029538
ELECTRON MICROSCOPYf_angle_d0.43112933
ELECTRON MICROSCOPYf_dihedral_angle_d9.0893488
ELECTRON MICROSCOPYf_chiral_restr0.0431468
ELECTRON MICROSCOPYf_plane_restr0.0031668

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