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- EMDB-70789: DDB1-CRBN-CK1a with lenalidomide and SB-405483 (Focused map) -

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Basic information

Entry
Database: EMDB / ID: EMD-70789
TitleDDB1-CRBN-CK1a with lenalidomide and SB-405483 (Focused map)
Map data
Sample
  • Complex: DDB1(BPB deleted)-CRBN complex with Casein kinase 1 alpha, lenalidomide, and SB-405483
    • Protein or peptide: DNA damage binding protein 1 (DDB1)
    • Protein or peptide: Cereblon (CRBN)
    • Protein or peptide: Casein kinase 1 alpha (CK1a)
KeywordsE3 ligases / Cullin RING Ligase / CRL4 / Cereblon / CRBN / molecular glues / IMiDs / LIGASE
Function / homology
Function and homology information


intermediate filament cytoskeleton organization / Activation of SMO / negative regulation of monoatomic ion transmembrane transport / negative regulation of NLRP3 inflammasome complex assembly / cellular response to nutrient / beta-catenin destruction complex / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / Beta-catenin phosphorylation cascade ...intermediate filament cytoskeleton organization / Activation of SMO / negative regulation of monoatomic ion transmembrane transport / negative regulation of NLRP3 inflammasome complex assembly / cellular response to nutrient / beta-catenin destruction complex / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / Disassembly of the destruction complex and recruitment of AXIN to the membrane / UV-damage excision repair / Maturation of nucleoprotein / 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 / positive regulation of Rho protein signal transduction / Cul4B-RING E3 ubiquitin ligase complex / Golgi organization / 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 TORC1 signaling / positive regulation of gluconeogenesis / sperm principal piece / nucleotide-excision repair / positive regulation of protein-containing complex assembly / negative regulation of canonical Wnt signaling pathway / Recognition of DNA damage by PCNA-containing replication complex / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / regulation of circadian rhythm / Degradation of beta-catenin by the destruction complex / kinetochore / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / spindle / 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 / positive regulation of proteasomal ubiquitin-dependent protein catabolic 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 / protein phosphorylation / cell surface receptor signaling pathway / chromosome, telomeric region / protein kinase activity / non-specific serine/threonine protein kinase / cilium / nuclear speck / ciliary basal body / viral protein processing / protein ubiquitination / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / apoptotic process / DNA damage response / centrosome / negative regulation of apoptotic process / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / signal transduction / protein-containing complex / extracellular space
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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Casein kinase I isoform alpha / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsRizvi Z / Lander GC
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM143805 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 23, 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_70789.png

Downloads & links

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Map

FileDownload / File: emd_70789.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 320 pix.
= 236.8 Å		0.74 Å/pix.
x 320 pix.
= 236.8 Å		0.74 Å/pix.
x 320 pix.
= 236.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.74 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0659
Minimum - Maximum-1.0054208 - 1.5182039
Average (Standard dev.)-0.00019220416 (±0.022246176)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 236.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_70789_msk_1.map
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Additional map: #1

Fileemd_70789_additional_1.map
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Half map: #1

Fileemd_70789_half_map_1.map
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Half map: #2

Fileemd_70789_half_map_2.map
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Sample components

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Entire : DDB1(BPB deleted)-CRBN complex with Casein kinase 1 alpha, lenali...

EntireName: DDB1(BPB deleted)-CRBN complex with Casein kinase 1 alpha, lenalidomide, and SB-405483
Components
  • Complex: DDB1(BPB deleted)-CRBN complex with Casein kinase 1 alpha, lenalidomide, and SB-405483
    • Protein or peptide: DNA damage binding protein 1 (DDB1)
    • Protein or peptide: Cereblon (CRBN)
    • Protein or peptide: Casein kinase 1 alpha (CK1a)

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Supramolecule #1: DDB1(BPB deleted)-CRBN complex with Casein kinase 1 alpha, lenali...

SupramoleculeName: DDB1(BPB deleted)-CRBN complex with Casein kinase 1 alpha, lenalidomide, and SB-405483
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 183.66303 KDa

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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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Macromolecule #3: Casein kinase 1 alpha (CK1a)

MacromoleculeName: Casein kinase 1 alpha (CK1a) / type: protein_or_peptide / ID: 3 / Details: tagless / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
SequenceString: MASSSGSKAE FIVGGKYKLV RKIGSGSFGD IYLAINITNG EEVAVKLESQ KARHPQLLYE SKLYKILQGG VGIPHIRWYG QEKDYNVLVM DLLGPSLEDL FNFCSRRFTM KTVLMLADQM ISRIEYVHTK NFIHRDIKPD NFLMGIGRHC NKLFLIDFGL AKKYRDNRTR ...String:
MASSSGSKAE FIVGGKYKLV RKIGSGSFGD IYLAINITNG EEVAVKLESQ KARHPQLLYE SKLYKILQGG VGIPHIRWYG QEKDYNVLVM DLLGPSLEDL FNFCSRRFTM KTVLMLADQM ISRIEYVHTK NFIHRDIKPD NFLMGIGRHC NKLFLIDFGL AKKYRDNRTR QHIPYREDKN LTGTARYASI NAHLGIEQSR RDDMESLGYV LMYFNRTSLP WQGLKAATKK QKYEKISEKK MSTPVEVLCK GFPAEFAMYL NYCRGLRFEE APDYMYLRQL FRILFRTLNH QYDYTFDWTM LKQKAAQQAA SSSGQGQQAQ TPTGKQTDKT KSNMKGF

UniProtKB: Casein kinase I isoform alpha

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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
Component:
ConcentrationFormulaName
10.0 mMC8H18N2O4SHEPES
240.0 mMNaClSodium Chloride
3.0 mMC9H15O6PTCEP

Details: 10mM HEPES, 240mM NaCl, 3mM TCEP
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 100.1 / 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
DetailsThe protein complex was incubated with IMiD Leanlidomide and an allosteric binder SB-405483 was incubated at 1:13:20 for 30 minutes and then frozen on 1.2/1.3 Au grids

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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: 5381 / 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 magnification: 189189 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 19000
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

Particle selectionNumber selected: 3444252
CTF correctionSoftware - Name: cryoSPARC (ver. 4.6.2) / Type: PHASE FLIPPING ONLY
Startup modelType of model: INSILICO MODEL / In silico model: AB INITIO RECONSTRUCTION
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.2) / Number images used: 221293
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2)
Details: Ab initio reconstruction, heterogeneous refinement, and homogeneous refinement
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2) / Details: Non-uniform refinement
Final 3D classificationNumber classes: 6 / Software - Name: cryoSPARC (ver. 4.6.2)
FSC plot (resolution estimation)

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