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- EMDB-47269: Ternary complex of CRBN-DDB1-PDE6D with FPFT-2216 -

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Entry
Database: EMDB / ID: EMD-47269
TitleTernary complex of CRBN-DDB1-PDE6D with FPFT-2216
Map data
Sample
  • Complex: Ternary complex of CRBN-DDB1-PDE6D with FPFT-2216
    • Protein or peptide: Protein cereblon
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta
  • Ligand: ZINC ION
  • Ligand: (3S)-3-[(4M)-4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione
KeywordsCRBN / molecular glue / E3 ligase / PDE6D / LIGASE
Function / homology
Function and homology information


ARL13B-mediated ciliary trafficking of INPP5E / GTPase inhibitor activity / 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 / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition ...ARL13B-mediated ciliary trafficking of INPP5E / GTPase inhibitor activity / 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 / Cul4-RING E3 ubiquitin ligase complex / 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 / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of reproductive process / negative regulation of developmental process / locomotory exploration behavior / 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 / visual perception / positive regulation of gluconeogenesis / cytoplasmic vesicle membrane / 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 / RAS processing / small GTPase binding / Wnt signaling pathway / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / site of double-strand break / Neddylation / ubiquitin-dependent protein catabolic process / cytoplasmic vesicle / protein-macromolecule adaptor activity / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / cytoskeleton / chromosome, telomeric region / protein ubiquitination / cilium / DNA repair / intracellular membrane-bounded organelle / apoptotic process / DNA damage response / negative regulation of apoptotic process / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / protein-containing complex / extracellular space / DNA binding / extracellular exosome / nucleoplasm / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
Retinal rod rhodopsin-sensitive cGMP 3', 5'-cyclic phosphodiesterase, delta subunit / GMP phosphodiesterase, delta subunit / GMP phosphodiesterase, delta subunit superfamily / GMP-PDE, delta subunit / 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 ...Retinal rod rhodopsin-sensitive cGMP 3', 5'-cyclic phosphodiesterase, delta subunit / GMP phosphodiesterase, delta subunit / GMP phosphodiesterase, delta subunit superfamily / GMP-PDE, delta subunit / 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 / Immunoglobulin E-set / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsBaek K / Fischer ES
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA214608 United States
Damon Runyon Cancer Research FoundationDRG-2514-24 United States
CitationJournal: Nat Commun / Year: 2025
Title: Unveiling the hidden interactome of CRBN molecular glues.
Authors: Kheewoong Baek / Rebecca J Metivier / Shourya S Roy Burman / Jonathan W Bushman / Hojong Yoon / Ryan J Lumpkin / Julia K Ryan / Dinah M Abeja / Megha Lakshminarayan / Hong Yue / Samuel Ojeda ...Authors: Kheewoong Baek / Rebecca J Metivier / Shourya S Roy Burman / Jonathan W Bushman / Hojong Yoon / Ryan J Lumpkin / Julia K Ryan / Dinah M Abeja / Megha Lakshminarayan / Hong Yue / Samuel Ojeda / Yuan Xiong / Jianwei Che / Alyssa L Verano / Anna M Schmoker / Nathanael S Gray / Katherine A Donovan / Eric S Fischer /
Abstract: Induced proximity by molecular glues refers to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of molecular ...Induced proximity by molecular glues refers to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of molecular glues remains challenging, unbiased discovery methods are necessary to discover new chemical targets. Here we establish a high throughput affinity proteomics workflow leveraging E3 ligase activity-impaired CRBN-DDB1ΔB in cell lysates for the unbiased identification of molecular glue targets. By mapping the interaction landscape of CRBN-binding molecular glues, we unveil 298 protein targets and demonstrate the utility of enrichment methods for identifying targets overlooked by established methods. We use a computational workflow to estimate target confidence and perform biochemical and structural validation of uncharacterized neo-substrates. We further identify a lead compound for the previously untargeted non-zinc finger PPIL4 through a biochemical screen. Our study provides a comprehensive inventory of targets chemically recruited to CRBN and delivers a robust and scalable workflow for identifying drug-induced protein interactions in cell lysates.
History
DepositionOct 10, 2024-
Header (metadata) releaseAug 6, 2025-
Map releaseAug 6, 2025-
UpdateAug 6, 2025-
Current statusAug 6, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47269.png

Downloads & links

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Map

FileDownload / File: emd_47269.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 288 pix.
= 316.8 Å		1.1 Å/pix.
x 288 pix.
= 316.8 Å		1.1 Å/pix.
x 288 pix.
= 316.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
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Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0017076522 - 2.473967
Average (Standard dev.)0.0006128847 (±0.018030921)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 316.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_47269_msk_1.map
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Additional map: #2

Fileemd_47269_additional_1.map
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Additional map: #1

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Half map: #2

Fileemd_47269_half_map_1.map
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Half map: #1

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Sample components

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Entire : Ternary complex of CRBN-DDB1-PDE6D with FPFT-2216

EntireName: Ternary complex of CRBN-DDB1-PDE6D with FPFT-2216
Components
  • Complex: Ternary complex of CRBN-DDB1-PDE6D with FPFT-2216
    • Protein or peptide: Protein cereblon
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta
  • Ligand: ZINC ION
  • Ligand: (3S)-3-[(4M)-4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione

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Supramolecule #1: Ternary complex of CRBN-DDB1-PDE6D with FPFT-2216

SupramoleculeName: Ternary complex of CRBN-DDB1-PDE6D with FPFT-2216 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.747805 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GSMAGEGDQQ DAAHNMGNHL PLLPAESEEE DEMEVEDQDS KEAKKPNIIN FDTSLPTSHT YLGADMEEFH GRTLHDDDSC QVIPVLPQV MMILIPGQTL PLQLFHPQEV SMVRNLIQKD RTFAVLAYSN VQEREAQFGT TAEIYAYREE QDFGIEIVKV K AIGRQRFK ...String:
GSMAGEGDQQ DAAHNMGNHL PLLPAESEEE DEMEVEDQDS KEAKKPNIIN FDTSLPTSHT YLGADMEEFH GRTLHDDDSC QVIPVLPQV MMILIPGQTL PLQLFHPQEV SMVRNLIQKD RTFAVLAYSN VQEREAQFGT TAEIYAYREE QDFGIEIVKV K AIGRQRFK VLELRTQSDG IQQAKVQILP ECVLPSTMSA VQLESLNKCQ IFPSKPVSRE DQCSYKWWQK YQKRKFHCAN LT SWPRWLY SLYDAETLMD RIKKQLREWD ENLKDDSLPS NPIDFSYRVA ACLPIDDVLR IQLLKIGSAI QRLRCELDIM NKC TSLCCK QCQETEITTK NEIFSLSLCG PMAAYVNPHG YVHETLTVYK ACNLNLIGRP STEHSWFPGY AWTVAQCKIC ASHI GWKFT ATKKDMSPQK FWGLTRSALL PTIPDTEDEI SPDKVILCL

UniProtKB: Protein cereblon

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Macromolecule #2: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 2 / Details: del 396-705 with GNGNSG linker / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.618383 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GGRMSYNYVV TAQKPTAVNG CVTGHFTSAE DLNLLIAKNT RLEIYVVTAE GLRPVKEVGM YGKIAVMELF RPKGESKDLL FILTAKYNA CILEYKQSGE SIDIITRAHG NVQDRIGRPS ETGIIGIIDP ECRMIGLRLY DGLFKVIPLD RDNKELKAFN I RLEELHVI ...String:
GGRMSYNYVV TAQKPTAVNG CVTGHFTSAE DLNLLIAKNT RLEIYVVTAE GLRPVKEVGM YGKIAVMELF RPKGESKDLL FILTAKYNA CILEYKQSGE SIDIITRAHG NVQDRIGRPS ETGIIGIIDP ECRMIGLRLY DGLFKVIPLD RDNKELKAFN I RLEELHVI DVKFLYGCQA PTICFVYQDP QGRHVKTYEV SLREKEFNKG PWKQENVEAE ASMVIAVPEP FGGAIIIGQE SI TYHNGDK YLAIAPPIIK QSTIVCHNRV DPNGSRYLLG DMEGRLFMLL LEKEEQMDGT VTLKDLRVEL LGETSIAECL TYL DNGVVF VGSRLGDSQL VKLNVDSNEQ GSYVVAMETF TNLGPIVDMC VVDLERQGQG QLVTCSGAFK EGSLRIIRNG IGGN GNSGE IQKLHIRTVP LYESPRKICY QEVSQCFGVL SSRIEVQDTS GGTTALRPSA STQALSSSVS SSKLFSSSTA PHETS FGEE VEVHNLLIID QHTFEVLHAH QFLQNEYALS LVSCKLGKDP NTYFIVGTAM VYPEEAEPKQ GRIVVFQYSD GKLQTV AEK EVKGAVYSMV EFNGKLLASI NSTVRLYEWT TEKELRTECN HYNNIMALYL KTKGDFILVG DLMRSVLLLA YKPMEGN FE EIARDFNPNW MSAVEILDDD NFLGAENAFN LFVCQKDSAA TTDEERQHLQ EVGLFHLGEF VNVFCHGSLV MQNLGETS T PTQGSVLFGT VNGMIGLVTS LSESWYNLLL DMQNRLNKVI KSVGKIEHSF WRSFHTERKT EPATGFIDGD LIESFLDIS RPKMQEVVAN LQYDDGSGMK REATADDLIK VVEELTRIH

UniProtKB: DNA damage-binding protein 1

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Macromolecule #3: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiestera...

MacromoleculeName: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.581094 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
GGRSAKDERA REILRGFKLN WMNLRDAETG KILWQGTEDL SVPGVEHEAR VPKKILKCKA VSRELNFSST EQMEKFRLEQ KVYFKGQCL EEWFFEFGFV IPNSTNTWQS LIEAAPESQM MPASVLTGNV IIETKFFDDD LLVSTSRVRL FYV

UniProtKB: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: (3S)-3-[(4M)-4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]pip...

MacromoleculeName: (3S)-3-[(4M)-4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1BC8
Molecular weightTheoretical: 292.314 Da

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 51.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 515636
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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