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- PDB-9dwv: Ternary complex of CRBN-DDB1-PPIL4 RRM domain with FPFT-2216 -

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Basic information

Entry
Database: PDB / ID: 9dwv
TitleTernary complex of CRBN-DDB1-PPIL4 RRM domain with FPFT-2216
Components
  • DNA damage-binding protein 1
  • Peptidyl-prolyl cis-trans isomerase-like 4
  • Protein cereblon
KeywordsLIGASE / CRBN / molecular glue / E3 ligase / PPIL4
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 / regulation of cell cycle phase transition / locomotory exploration behavior / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / regulation of cellular response to stress / limb development / viral release from host cell / cullin family protein binding / 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 / mRNA Splicing - Major Pathway / regulation of embryonic development / replication fork processing / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / proteasomal protein catabolic process / mRNA splicing, via spliceosome / 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-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 / cellular response to UV / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / regulation of cell population proliferation / rhythmic process / site of double-strand break / Neddylation / Dengue Virus-Host Interactions / spermatogenesis / ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of apoptotic process / transmembrane transporter binding / protein-macromolecule adaptor activity / chromosome, telomeric region / protein ubiquitination / DNA repair / DNA damage response / nucleolus / protein-containing complex binding / perinuclear region of cytoplasm / protein-containing complex / DNA binding / : / RNA binding / extracellular exosome / nucleoplasm / membrane / metal ion binding / nucleus / 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 / 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 / PUA-like 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsBaek, K. / Fischer, E.S.
Funding support United States, 2items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 6, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: DNA damage-binding protein 1
B: Protein cereblon
C: Peptidyl-prolyl cis-trans isomerase-like 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)187,8285
Polymers187,4703
Non-polymers3582
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 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: 127097.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: DDB1 (masking away BPB domain, residues 396-705) / Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16531
#2: Protein Protein cereblon


Mass: 50747.805 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: Trichoplusia ni (cabbage looper) / References: UniProt: Q96SW2
#3: Protein Peptidyl-prolyl cis-trans isomerase-like 4 / PPIase / Cyclophilin-like protein PPIL4 / Rotamase PPIL4


Mass: 9624.897 Da / Num. of mol.: 1 / Fragment: RRM domain, residues 240-318
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPIL4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8WUA2, peptidylprolyl isomerase
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-A1BC8 / (3S)-3-[(4M)-4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione


Mass: 292.314 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H12N4O3S / 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 complex of CRBN-DDB1-PPIL4 RRM domain with FPFT-2216
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 54 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 219802 / Symmetry type: POINT

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