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- EMDB-47268: Ternary complex of CRBN-DDB1-PPIL4 RRM domain with FPFT-2216 -

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Entry
Database: EMDB / ID: EMD-47268
TitleTernary complex of CRBN-DDB1-PPIL4 RRM domain with FPFT-2216
Map dataPPIL4 RRM-FPFT2216-CRBN-DDB1 DeepEMhancer
Sample
  • Complex: Ternary complex of CRBN-DDB1-PPIL4 RRM domain with FPFT-2216
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Protein cereblon
    • Protein or peptide: Peptidyl-prolyl cis-trans isomerase-like 4
  • 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 / PPIL4 / LIGASE
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 / 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 ...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 / positive regulation of gluconeogenesis / mRNA Splicing - Major Pathway / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / 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 / 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 / DNA repair / 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 / RNA binding / extracellular exosome / nucleoplasm / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
PPIL4-like, cyclophilin domain / Cyclophilin-RNA interacting protein / 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 ...PPIL4-like, cyclophilin domain / Cyclophilin-RNA interacting protein / 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 / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain profile. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain / Cyclophilin type peptidyl-prolyl cis-trans isomerase/CLD / Cyclophilin-like domain superfamily / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
DNA damage-binding protein 1 / Peptidyl-prolyl cis-trans isomerase-like 4 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 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_47268.png

Downloads & links

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Map

FileDownload / File: emd_47268.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPPIL4 RRM-FPFT2216-CRBN-DDB1 DeepEMhancer
Projections & slices

Image control

Size
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Others
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

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.0017220937 - 1.8337038
Average (Standard dev.)0.00070188724 (±0.01904318)
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_47268_msk_1.map
Projections & Slices
AxesZYX

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Additional map: 3D refinement

Fileemd_47268_additional_1.map
Annotation3D refinement
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Additional map: sharpened map

Fileemd_47268_additional_2.map
Annotationsharpened map
Projections & Slices
AxesZYX

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Half map: halfmap1

Fileemd_47268_half_map_1.map
Annotationhalfmap1
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AxesZYX

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Histogram (log scale)

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Half map: halfmap2

Fileemd_47268_half_map_2.map
Annotationhalfmap2
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Sample components

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Entire : Ternary complex of CRBN-DDB1-PPIL4 RRM domain with FPFT-2216

EntireName: Ternary complex of CRBN-DDB1-PPIL4 RRM domain with FPFT-2216
Components
  • Complex: Ternary complex of CRBN-DDB1-PPIL4 RRM domain with FPFT-2216
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Protein cereblon
    • Protein or peptide: Peptidyl-prolyl cis-trans isomerase-like 4
  • 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-PPIL4 RRM domain with FPFT-2216

SupramoleculeName: Ternary complex of CRBN-DDB1-PPIL4 RRM domain 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: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 1 / Details: DDB1 (masking away BPB domain, residues 396-705) / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.097469 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
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 LRIIRNGIGI HEHA SIDLP GIKGLWPLRS DPNRETDDTL VLSFVGQTRV LMLNGEEVEE TELMGFVDDQ QTFFCGNVAH QQLIQITSAS VRLVS QEPK ALVSEWKEPQ AKNISVASCN SSQVVVAVGR ALYYLQIHPQ ELRQISHTEM EHEVACLDIT PLGDSNGLSP LCAIGL WTD ISARILKLPS FELLHKEMLG GEIIPRSILM TTFESSHYLL CALGDGALFY FGLNIETGLL SDRKKVTLGT QPTVLRT FR SLSTTNVFAC SDRPTVIYSS NHKLVFSNVN LKEVNYMCPL NSDGYPDSLA LANNSTLTIG TIDEIQKLHI RTVPLYES P RKICYQEVSQ CFGVLSSRIE VQDTSGGTTA LRPSASTQAL SSSVSSSKLF SSSTAPHETS FGEEVEVHNL LIIDQHTFE VLHAHQFLQN EYALSLVSCK LGKDPNTYFI VGTAMVYPEE AEPKQGRIVV FQYSDGKLQT VAEKEVKGAV YSMVEFNGKL LASINSTVR LYEWTTEKEL RTECNHYNNI MALYLKTKGD FILVGDLMRS VLLLAYKPME GNFEEIARDF NPNWMSAVEI L DDDNFLGA ENAFNLFVCQ KDSAATTDEE RQHLQEVGLF HLGEFVNVFC HGSLVMQNLG ETSTPTQGSV LFGTVNGMIG LV TSLSESW YNLLLDMQNR LNKVIKSVGK IEHSFWRSFH TERKTEPATG FIDGDLIESF LDISRPKMQE VVANLQYDDG SGM KREATA DDLIKVVEEL TRIH

UniProtKB: DNA damage-binding protein 1

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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: 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 #3: Peptidyl-prolyl cis-trans isomerase-like 4

MacromoleculeName: Peptidyl-prolyl cis-trans isomerase-like 4 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: peptidylprolyl isomerase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.624897 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
GGRNVLFVCK LNPVTTDEDL EIIFSRFGPI RSCEVIRDWK TGESLCYAFI EFEKEEDCEK AFFKMDNVLI DDRRIHVDFS QS

UniProtKB: Peptidyl-prolyl cis-trans isomerase-like 4

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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: 54.0 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: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 219802
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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