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- EMDB-52330: Cryo-EM structure of DDB1dB-CRBN-MRT-0031619, conformation 1 -

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Basic information

Entry
Database: EMDB / ID: EMD-52330
TitleCryo-EM structure of DDB1dB-CRBN-MRT-0031619, conformation 1
Map datamain map post-processed in RELION
Sample
  • Complex: Drug-induced ternary complex between two DDB1-CRBN moieties
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: (3~{S})-3-[3-oxidanylidene-5-[8-(phenylcarbonyl)-2,8-diazaspiro[4.5]decan-2-yl]-1~{H}-isoindol-2-yl]piperidine-2,6-dione
KeywordsTargeted protein degradation / molecular glue / ubiquitin proteasome system / CRBN / ubiquitin ligase / 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 / 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 / Cul4-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 / 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 / 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 / locomotory exploration behavior / viral release from host cell / cullin family protein binding / 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 / nucleotide-excision repair / positive regulation of protein-containing complex assembly / Recognition of DNA damage by PCNA-containing replication complex / regulation of circadian rhythm / 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 / Wnt signaling pathway / Formation of Incision Complex in GG-NER / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / 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 / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / damaged DNA binding / 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 / extracellular exosome / nucleoplasm / metal ion 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) / RSE1/DDB1/CPSF1 second beta-propeller ...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 / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.93 Å
AuthorsLangousis G / Hunkeler M / Chami M / Quan C / Townson S / Bonenfant D
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation.
Authors: Gerasimos Langousis / Pablo Gainza / Moritz Hunkeler / Despoina Kapsitidou / Etienne J Donckele / Stefano Annunziato / Lars Wiedmer / Katherine F M Jones / Bradley DeMarco / Chao Quan / ...Authors: Gerasimos Langousis / Pablo Gainza / Moritz Hunkeler / Despoina Kapsitidou / Etienne J Donckele / Stefano Annunziato / Lars Wiedmer / Katherine F M Jones / Bradley DeMarco / Chao Quan / Richard D Bunker / Kevin J Lumb / Bernhard Fasching / John C Castle / Sharon A Townson / Débora Bonenfant /
Abstract: Cereblon (CRBN) is an E3 ubiquitin ligase widely harnessed for targeted protein degradation (TPD). We report the discovery of a molecular glue degrader (MGD), MRT-31619, that drives homo-dimerization ...Cereblon (CRBN) is an E3 ubiquitin ligase widely harnessed for targeted protein degradation (TPD). We report the discovery of a molecular glue degrader (MGD), MRT-31619, that drives homo-dimerization of CRBN and promotes its fast, potent, and selective degradation by the ubiquitin proteasome system. Interestingly, the cryo-electron microscopy (cryo-EM) structure of the CRBN homodimer reveals a unique mechanism whereby two molecular glues assemble into a helix-like structure and drive ternary complex formation by mimicking a neosubstrate G-loop degron. This CRBN chemical knockout offers a valuable tool to elucidate the molecular mechanism of MGDs, to investigate its endogenous substrates and understand their physiological roles.
History
DepositionDec 13, 2024-
Header (metadata) releaseDec 3, 2025-
Map releaseDec 3, 2025-
UpdateDec 3, 2025-
Current statusDec 3, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52330.png

Downloads & links

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Map

FileDownload / File: emd_52330.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain map post-processed in RELION
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015
Minimum - Maximum-0.0895064 - 0.14036515
Average (Standard dev.)0.00013294707 (±0.0024463513)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_52330_msk_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Additional map: map postprocessed with deepEMhancer

Fileemd_52330_additional_1.map
Annotationmap postprocessed with deepEMhancer
Projections & Slices
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Histogram (log scale)

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Half map: half-map 1

Fileemd_52330_half_map_1.map
Annotationhalf-map 1
Projections & Slices
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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half-map 2

Fileemd_52330_half_map_2.map
Annotationhalf-map 2
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Sample components

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Entire : Drug-induced ternary complex between two DDB1-CRBN moieties

EntireName: Drug-induced ternary complex between two DDB1-CRBN moieties
Components
  • Complex: Drug-induced ternary complex between two DDB1-CRBN moieties
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: (3~{S})-3-[3-oxidanylidene-5-[8-(phenylcarbonyl)-2,8-diazaspiro[4.5]decan-2-yl]-1~{H}-isoindol-2-yl]piperidine-2,6-dione

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Supramolecule #1: Drug-induced ternary complex between two DDB1-CRBN moieties

SupramoleculeName: Drug-induced ternary complex between two DDB1-CRBN moieties
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 287 KDa

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Macromolecule #1: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.347078 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 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

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Macromolecule #2: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.24918 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: GAKKPNIINF DTSLPTSHTY LGADMEEFHG RTLHDDDSCQ VIPVLPQVMM ILIPGQTLPL QLFHPQEVSM VRNLIQKDRT FAVLAYSNV QEREAQFGTT AEIYAYREEQ DFGIEIVKVK AIGRQRFKVL ELRTQSDGIQ QAKVQILPEC VLPSTMSAVQ L ESLNKCQI ...String:
GAKKPNIINF DTSLPTSHTY LGADMEEFHG RTLHDDDSCQ VIPVLPQVMM ILIPGQTLPL QLFHPQEVSM VRNLIQKDRT FAVLAYSNV QEREAQFGTT AEIYAYREEQ DFGIEIVKVK AIGRQRFKVL ELRTQSDGIQ QAKVQILPEC VLPSTMSAVQ L ESLNKCQI FPSKPVSRED QCSYKWWQKY QKRKFHCANL TSWPRWLYSL YDAETLMDRI KKQLREWDEN LKDDSLPSNP ID FSYRVAA CLPIDDVLRI QLLKIGSAIQ RLRCELDIMN KCTSLCCKQC QETEITTKNE IFSLSLCGPM AAYVNPHGYV HET LTVYKA CNLNLIGRPS TEHSWFPGYA WTVAQCKICA SHIGWKFTAT KKDMSPQKFW GLTRSALLPT IPDTEDEISP DKVI LCL

UniProtKB: Protein cereblon

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: (3~{S})-3-[3-oxidanylidene-5-[8-(phenylcarbonyl)-2,8-diazaspiro[4...

MacromoleculeName: (3~{S})-3-[3-oxidanylidene-5-[8-(phenylcarbonyl)-2,8-diazaspiro[4.5]decan-2-yl]-1~{H}-isoindol-2-yl]piperidine-2,6-dione
type: ligand / ID: 4 / Number of copies: 2 / Formula: A1IW1
Molecular weightTheoretical: 486.562 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

Concentration9 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMhepesHEPES
100.0 mMnaclsodium chloride
0.5 mMTCEPTCEP
0.01 %DDMDDM

Details: Sample supplemented with DDM directly before vitrification
GridModel: Quantifoil R2/1 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 12 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.039 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 283 K / Instrument: LEICA EM GP / Details: LEICA EMGP2.

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Detailscollected with AFIS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 20582 / Average electron dose: 40.0 e/Å2 / Details: Movies with 52 frames
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 20.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 165000
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: 4802227 / Details: TOPAZ with general model
CTF correctionSoftware: (Name: CTFFIND (ver. 4.1.10), RELION (ver. 5.0)) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: RELION ab initio
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 203344
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0)
Final 3D classificationNumber classes: 8 / Avg.num./class: 552790 / Software - Name: RELION (ver. 5.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8tnq


Chain - Source name: PDB / Chain - Initial model type: experimental model
Detailsreal space refinement in COOT and phenix
RefinementSpace: REAL / Protocol: OTHER / Overall B value: 73 / Target criteria: real space cross correlation
Output model

PDB-9hpi:
Cryo-EM structure of DDB1dB-CRBN-MRT-0031619, conformation 1

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