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- EMDB-70777: DDB1-CRBN open local refinement -

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Basic information

Entry
Database: EMDB / ID: EMD-70777
TitleDDB1-CRBN open local refinement
Map dataLocal-refinement sharpened map
Sample
  • Complex: DDB1-CRBN
    • Protein or peptide: DNA damage binding protein 1 (DDB1)
    • Protein or peptide: Cereblon (CRBN)
KeywordsCereblon / E3 ligases / Cullin RING Ligase / CRL4 / molecular glues / IMiDs / 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 / WD40-repeat domain binding / regulation of mitotic cell cycle phase transition / limb development / 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 / UV-damage excision repair / biological process involved in interaction with symbiont / WD40-repeat domain binding / regulation of mitotic cell cycle phase transition / limb development / 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 / ectopic germ cell programmed cell death / positive regulation of Wnt signaling pathway / positive regulation of viral genome replication / negative regulation of protein-containing complex assembly / proteasomal protein catabolic process / sperm end piece / positive regulation of gluconeogenesis / sperm principal piece / 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 / sperm midpiece / rhythmic process / site of double-strand break / Neddylation / protein-macromolecule adaptor activity / ubiquitin-dependent protein catabolic process / 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 / membrane / nucleus / cytoplasm / cytosol
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 / 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: 2.4 Å
AuthorsRizvi Z / Lander GC
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM143805 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM154216 United States
CitationJournal: Nature / Year: 2026
Title: Identification of an allosteric site on the E3 ligase adapter cereblon.
Authors: Vanessa N Dippon / Zeba Rizvi / Anthony E Choudhry / Chun-Wa Chung / Ibrahim F Alkuraya / Wenqing Xu / Xavier B Tao / Anthony J Jurewicz / Jessica L Schneck / Wenqian Chen / Nicole M Curnutt ...Authors: Vanessa N Dippon / Zeba Rizvi / Anthony E Choudhry / Chun-Wa Chung / Ibrahim F Alkuraya / Wenqing Xu / Xavier B Tao / Anthony J Jurewicz / Jessica L Schneck / Wenqian Chen / Nicole M Curnutt / Farah Kabir / Kwok-Ho Chan / Markus A Queisser / Caterina Musetti / Han Dai / Gabriel C Lander / Andrew B Benowitz / Christina M Woo /
Abstract: Cereblon (CRBN) is the target of thalidomide derivatives that achieve therapeutic efficacy against some haematologic neoplasias by recruiting neosubstrates for degradation. Despite the intense ...Cereblon (CRBN) is the target of thalidomide derivatives that achieve therapeutic efficacy against some haematologic neoplasias by recruiting neosubstrates for degradation. Despite the intense investigation of orthosteric thalidomide derivatives, little is known about alternate binding sites on CRBN. Here we report an evolutionarily conserved cryptic allosteric binding site on CRBN. Small-molecule SB-405483 binds the allosteric site to cooperatively enhance the binding of orthosteric ligands and alter their neosubstrate degradation profiles. A survey of over 100 orthosteric ligands and their degradation targets reveals trends in the classes of compounds and neosubstrates in which degradation outcomes are enhanced or inhibited by SB-405483. Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBN to a novel CRBN and increasing the CRBN state. The discovery of a cryptic allosteric binding site on CRBN that alters the functional effects of orthosteric ligands opens new directions with broad implications for improving the selectivity and efficacy of CRBN therapeutics.
History
DepositionMay 22, 2025-
Header (metadata) releaseNov 19, 2025-
Map releaseNov 19, 2025-
UpdateFeb 4, 2026-
Current statusFeb 4, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70777.png

Downloads & links

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Map

FileDownload / File: emd_70777.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal-refinement sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 300 pix.
= 222. Å		0.74 Å/pix.
x 300 pix.
= 222. Å		0.74 Å/pix.
x 300 pix.
= 222. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.74 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.194
Minimum - Maximum-1.6501945 - 2.946118
Average (Standard dev.)-0.00033756977 (±0.021582298)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 222.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Local-refinement unsharpened map

Fileemd_70777_additional_1.map
AnnotationLocal-refinement unsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Local-refinement halfmap A

Fileemd_70777_half_map_1.map
AnnotationLocal-refinement halfmap A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Local-refinement halfmap B

Fileemd_70777_half_map_2.map
AnnotationLocal-refinement halfmap B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : DDB1-CRBN

EntireName: DDB1-CRBN
Components
  • Complex: DDB1-CRBN
    • Protein or peptide: DNA damage binding protein 1 (DDB1)
    • Protein or peptide: Cereblon (CRBN)

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Supramolecule #1: DDB1-CRBN

SupramoleculeName: DDB1-CRBN / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: DNA damage binding protein 1 (DDB1)

MacromoleculeName: DNA damage binding protein 1 (DDB1) / type: protein_or_peptide / ID: 1
Details: The BPB domain is truncated (396-705 truncation with addition of a GNGNSG linker between BPA and BPC) from DDB1 and co-expressed with Cereblon (CRBN) in SF9 expression system.
Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
SequenceString: MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACILE YKQSGESIDI ITRAHGNVQD RIGRPSETGI IGIIDPECRM IGLRLYDGLF KVIPLDRDNK ELKAFNIRLE ELHVIDVKFL ...String:
MSYNYVVTAQ KPTAVNGCVT GHFTSAEDLN LLIAKNTRLE IYVVTAEGLR PVKEVGMYGK IAVMELFRPK GESKDLLFIL TAKYNACILE YKQSGESIDI ITRAHGNVQD RIGRPSETGI IGIIDPECRM IGLRLYDGLF KVIPLDRDNK ELKAFNIRLE ELHVIDVKFL YGCQAPTICF VYQDPQGRHV KTYEVSLREK EFNKGPWKQE NVEAEASMVI AVPEPFGGAI IIGQESITYH NGDKYLAIAP PIIKQSTIVC HNRVDPNGSR YLLGDMEGRL FMLLLEKEEQ MDGTVTLKDL RVELLGETSI AECLTYLDNG VVFVGSRLGD SQLVKLNVDS NEQGSYVVAM ETFTNLGPIV DMCVVDLERQ GQGQLVTCSG AFKEGSLRII RNGIGGNGNS GEIQKLHIRT VPLYESPRKI CYQEVSQCFG VLSSRIEVQD TSGGTTALRP SASTQALSSS VSSSKLFSSS TAPHETSFGE EVEVHNLLII DQHTFEVLHA HQFLQNEYAL SLVSCKLGKD PNTYFIVGTA MVYPEEAEPK QGRIVVFQYS DGKLQTVAEK EVKGAVYSMV EFNGKLLASI NSTVRLYEWT TEKELRTECN HYNNIMALYL KTKGDFILVG DLMRSVLLLA YKPMEGNFEE IARDFNPNWM SAVEILDDDN FLGAENAFNL FVCQKDSAAT TDEERQHLQE VGLFHLGEFV NVFCHGSLVM QNLGETSTPT QGSVLFGTVN GMIGLVTSLS ESWYNLLLDM QNRLNKVIKS VGKIEHSFWR SFHTERKTEP ATGFIDGDLI ESFLDISRPK MQEVVANLQY DDGSGMKREA TADDLIKVVE ELTRIH

UniProtKB: DNA damage-binding protein 1

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Macromolecule #2: Cereblon (CRBN)

MacromoleculeName: Cereblon (CRBN) / type: protein_or_peptide / ID: 2 / Details: 6X His tag at N-terminus / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
SequenceString: MHHHHHHMAG EGDQQDAAHN MGNHLPLLPA ESEEEDEMEV EDQDSKEAKK PNIINFDTSL PTSHTYLGAD MEEFHGRTLH DDDSCQVIPV LPQVMMILIP GQTLPLQLFH PQEVSMVRNL IQKDRTFAVL AYSNVQEREA QFGTTAEIYA YREEQDFGIE IVKVKAIGRQ ...String:
MHHHHHHMAG EGDQQDAAHN MGNHLPLLPA ESEEEDEMEV EDQDSKEAKK PNIINFDTSL PTSHTYLGAD MEEFHGRTLH DDDSCQVIPV LPQVMMILIP GQTLPLQLFH PQEVSMVRNL IQKDRTFAVL AYSNVQEREA QFGTTAEIYA YREEQDFGIE IVKVKAIGRQ RFKVLELRTQ SDGIQQAKVQ ILPECVLPST MSAVQLESLN KCQIFPSKPV SREDQCSYKW WQKYQKRKFH CANLTSWPRW LYSLYDAETL MDRIKKQLRE WDENLKDDSL PSNPIDFSYR VAACLPIDDV LRIQLLKIGS AIQRLRCELD IMNKCTSLCC KQCQETEITT KNEIFSLSLC GPMAAYVNPH GYVHETLTVY KACNLNLIGR PSTEHSWFPG YAWTVAQCKI CASHIGWKFT ATKKDMSPQK FWGLTRSALL PTIPDTEDEI SPDKVILCL

UniProtKB: Protein cereblon

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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

Concentration0.5 mg/mL
BufferpH: 7
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 100 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 12 sec. / Pretreatment - Atmosphere: OTHER / Pretreatment - Pressure: 0.0239980266 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277.15 K / Instrument: HOMEMADE PLUNGER

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
TemperatureMin: 70.0 K / Max: 77.0 K
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 4783 / Average exposure time: 4.08 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated defocus max: 3.0 µm / Calibrated defocus min: 0.1 µm / Calibrated magnification: 189189 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 12.0 µm / Nominal defocus min: 8.0 µm / Nominal magnification: 190000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.6.2) / Type: PHASE FLIPPING ONLY
Startup modelType of model: INSILICO MODEL / In silico model: Ab initio
Final reconstructionNumber classes used: 3 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.2) / Number images used: 1023173
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2) / Details: homogeneous and heterogeneous refinement
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2) / Details: non-uniform refinement
Final 3D classificationNumber classes: 6 / Avg.num./class: 451959 / Software - Name: cryoSPARC (ver. 4.6.2)
FSC plot (resolution estimation)

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