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- EMDB-72160: Cryo-EM structure of ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1 ... -

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Entry
Database: EMDB / ID: EMD-72160
TitleCryo-EM structure of ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1 (molecular glue degrader)
Map data
Sample
  • Complex: ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1
    • Protein or peptide: DNA-binding protein Ikaros
    • Protein or peptide: Protein cereblon
    • Protein or peptide: DNA damage-binding protein 1
  • Ligand: ZINC ION
  • Ligand: 1-(3-chloro-4-methylphenyl)-3-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea
KeywordsCereblon / degrader / Ikaros / IKZF1 / DDB1 / molecular glue / LIGASE
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
DNA-binding protein Ikaros / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.94 Å
AuthorsZhu J / Pagarigan BE / Tran ET
Funding support1 items
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, 2025-
Header (metadata) releaseOct 1, 2025-
Map releaseOct 1, 2025-
UpdateOct 1, 2025-
Current statusOct 1, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72160.png

Downloads & links

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Map

FileDownload / File: emd_72160.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 256 pix.
= 267.52 Å		1.05 Å/pix.
x 256 pix.
= 267.52 Å		1.05 Å/pix.
x 256 pix.
= 267.52 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.045 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.15068899 - 0.26210892
Average (Standard dev.)-0.00009332181 (±0.0062053795)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 267.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_72160_msk_1.map
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Half map: #2

Fileemd_72160_half_map_1.map
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Half map: #1

Fileemd_72160_half_map_2.map
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Sample components

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Entire : ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1

EntireName: ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1
Components
  • Complex: ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1
    • Protein or peptide: DNA-binding protein Ikaros
    • Protein or peptide: Protein cereblon
    • Protein or peptide: DNA damage-binding protein 1
  • Ligand: ZINC ION
  • Ligand: 1-(3-chloro-4-methylphenyl)-3-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea

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Supramolecule #1: ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1

SupramoleculeName: ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 / Details: ternary complex of three proteins and CC-885
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 150 KDa

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Macromolecule #1: DNA-binding protein Ikaros

MacromoleculeName: DNA-binding protein Ikaros / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.731428 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GSLPNGKLKC DICGIICIGP NVLMVHKRSH TGERPFQCNQ CGASFTQKGN LLRHIKLHSG EKPFKCHLCN YACRRRDALT GHLRTHS

UniProtKB: DNA-binding protein Ikaros

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Macromolecule #2: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.581984 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYYHHHHHH DYDIPTTGLV PRGSMMAGEG DQQDAAHNMG NHLPLLPAES EEEDEMEVED QDSKEAKKPN IINFDTSLPT SHTYLGADM EEFHGRTLHD DDSCQVIPVL PQVMMILIPG QTLPLQLFHP QEVSMVRNLI QKDRTFAVLA YSNVQEREAQ F GTTAEIYA ...String:
MSYYHHHHHH DYDIPTTGLV PRGSMMAGEG DQQDAAHNMG NHLPLLPAES EEEDEMEVED QDSKEAKKPN IINFDTSLPT SHTYLGADM EEFHGRTLHD DDSCQVIPVL PQVMMILIPG QTLPLQLFHP QEVSMVRNLI QKDRTFAVLA YSNVQEREAQ F GTTAEIYA YREEQDFGIE IVKVKAIGRQ RFKVLELRTQ SDGIQQAKVQ ILPECVLPST MSAVQLESLN KCQIFPSKPV SR EDQCSYK WWQKYQKRKF HCANLTSWPR WLYSLYDAET LMDRIKKQLR EWDENLKDDS LPSNPIDFSY RVAACLPIDD VLR IQLLKI GSAIQRLRCE LDIMNKCTSL CCKQCQETEI TTKNEIFSLS LCGPMAAYVN PHGYVHETLT VYKACNLNLI GRPS TEHSW FPGYAWTVAQ CKICASHIGW KFTATKKDMS PQKFWGLTRS ALLPTIPDTE DEISPDKVIL CL

UniProtKB: Protein cereblon

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Macromolecule #3: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.347078 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACIL EYKQSGESID IITRAHGNVQ DRIGRPSETG IIGIIDPECR MIGLRLYDGL FKVIPLDRDN KELKAFNIRL E ELHVIDVK ...String:
MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACIL EYKQSGESID IITRAHGNVQ DRIGRPSETG IIGIIDPECR MIGLRLYDGL FKVIPLDRDN KELKAFNIRL E ELHVIDVK FLYGCQAPTI CFVYQDPQGR HVKTYEVSLR EKEFNKGPWK QENVEAEASM VIAVPEPFGG AIIIGQESIT YH NGDKYLA IAPPIIKQST IVCHNRVDPN GSRYLLGDME GRLFMLLLEK EEQMDGTVTL KDLRVELLGE TSIAECLTYL DNG VVFVGS RLGDSQLVKL NVDSNEQGSY VVAMETFTNL GPIVDMCVVD LERQGQGQLV TCSGAFKEGS LRIIRNGIGG NGNS GEIQK LHIRTVPLYE SPRKICYQEV SQCFGVLSSR IEVQDTSGGT TALRPSASTQ ALSSSVSSSK LFSSSTAPHE TSFGE EVEV HNLLIIDQHT FEVLHAHQFL QNEYALSLVS CKLGKDPNTY FIVGTAMVYP EEAEPKQGRI VVFQYSDGKL QTVAEK EVK GAVYSMVEFN GKLLASINST VRLYEWTTEK ELRTECNHYN NIMALYLKTK GDFILVGDLM RSVLLLAYKP MEGNFEE IA RDFNPNWMSA VEILDDDNFL GAENAFNLFV CQKDSAATTD EERQHLQEVG LFHLGEFVNV FCHGSLVMQN LGETSTPT Q GSVLFGTVNG MIGLVTSLSE SWYNLLLDMQ NRLNKVIKSV GKIEHSFWRS FHTERKTEPA TGFIDGDLIE SFLDISRPK MQEVVANLQY DDGSGMKREA TADDLIKVVE ELTRIH

UniProtKB: DNA damage-binding protein 1, DNA damage-binding protein 1

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: 1-(3-chloro-4-methylphenyl)-3-({2-[(3S)-2,6-dioxopiperidin-3-yl]-...

MacromoleculeName: 1-(3-chloro-4-methylphenyl)-3-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea
type: ligand / ID: 5 / Number of copies: 1 / Formula: 85C
Molecular weightTheoretical: 440.88 Da
Chemical component information

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

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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

Concentration3.5 mg/mL
BufferpH: 7
Component:
ConcentrationNameFormula
10.0 mM(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethanesulfonic acid)
240.0 mMsodium chlorideNaCl
3.0 mMtris(2-carboxyethyl)phosphine
0.3 %Dimethyl sulfoxide
0.001 %Lauryl Maltose Neopentyl Glycol
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV / Details: blot time 4 sec blot force 4.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 9754 / Average exposure time: 3.2 sec. / Average electron dose: 29.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.6 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 75000
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

Particle selectionNumber selected: 20365602
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8d81

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 84299
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationSoftware - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8d81


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9q2d:
Cryo-EM structure of ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1 (molecular glue degrader)

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