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- EMDB-47111: cryo-EM structure of human Cereblon/DDB1 in complex with a non-tr... -

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Basic information

Entry
Database: EMDB / ID: EMD-47111
Titlecryo-EM structure of human Cereblon/DDB1 in complex with a non-traditional CRBN binder
Map datacryosparc NU refinement map
Sample
  • Complex: CREBN-DDB1 plus a non-traditional CRBN binder
    • Protein or peptide: Protein cereblon
    • Protein or peptide: DNA damage-binding protein 1
  • Ligand: ZINC ION
  • Ligand: (3R)-3-{1-methyl-6-[(piperidin-4-yl)amino]-1H-indazol-3-yl}piperidine-2,6-dione
KeywordsCRL4 / UBIQUITIN / E3 / CEREBLON / 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 / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / 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 / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / 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 / 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 / positive regulation of protein catabolic process / Gap-filling DNA repair synthesis and ligation in TC-NER / cellular response to UV / rhythmic process / site of double-strand break / Neddylation / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / damaged DNA binding / chromosome, telomeric region / protein ubiquitination / DNA repair / apoptotic process / DNA damage response / protein-containing complex binding / negative regulation of apoptotic process / nucleolus / perinuclear region of cytoplasm / protein-containing complex / DNA binding / extracellular space / 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: 3.0 Å
AuthorsZhu J / Pagarigan B
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: ACS Med Chem Lett / Year: 2025
Title: Development of a Buchwald-Hartwig Amination for an Accelerated Library Synthesis of Cereblon Binders.
Authors: Anastasia Lejava / Giulianna A Miseo / Thomas Phan / Jinyi Zhu / Hannah L Powers / Jianqing Li / Deborah S Mortensen / Christoph W Zapf / Gody Khambatta / Jennifer Buenviaje / Natalie Holmberg-Douglas /
Abstract: In recent years, targeted protein degradation (TPD) has emerged as a powerful therapeutic modality utilizing both heterobifunctional ligand-directed degraders (LDDs) and molecular glues (e.g., ...In recent years, targeted protein degradation (TPD) has emerged as a powerful therapeutic modality utilizing both heterobifunctional ligand-directed degraders (LDDs) and molecular glues (e.g., CELMoDs) to recruit E3 ligases for inducing polyubiquitination and subsequent proteasomal degradation of target proteins. The immunomodulatory drugs lenalidomide and pomalidomide bind to cereblon (CRBN), a substrate receptor of the CRL4A E3 ligase complex, to initiate degradation of neosubstrates critical for cell survival. Recently, nonlenalidomide or pomalidomide CRBN binders, known as alternate glutarimides, have gained popularity, offering potential degraders with varying physicochemical properties. Specifically, 3-substituted indazole derivatives have emerged as potent CRBN binders. We developed conditions for the direct cross-coupling of unprotected glutarimides with amines, streamlining the synthesis of alternative CRBN binders. This manuscript describes the rapid synthesis of 30 CRBN binders, their characterization as potential degraders and a cryo-EM structure of the CRBN/DDB1 with a representative compound ().
History
DepositionSep 23, 2024-
Header (metadata) releaseDec 25, 2024-
Map releaseDec 25, 2024-
UpdateJan 29, 2025-
Current statusJan 29, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47111.png

Downloads & links

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Map

FileDownload / File: emd_47111.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryosparc NU refinement map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 220 pix.
= 229.9 Å		1.05 Å/pix.
x 220 pix.
= 229.9 Å		1.05 Å/pix.
x 220 pix.
= 229.9 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.045 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.9943792 - 2.0171804
Average (Standard dev.)-0.004064133 (±0.06395819)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 229.9 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: cryosparc NU refinement half-A map

Fileemd_47111_half_map_1.map
Annotationcryosparc NU refinement half-A map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: cryosparc NU refinement half-B map

Fileemd_47111_half_map_2.map
Annotationcryosparc NU refinement half-B map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CREBN-DDB1 plus a non-traditional CRBN binder

EntireName: CREBN-DDB1 plus a non-traditional CRBN binder
Components
  • Complex: CREBN-DDB1 plus a non-traditional CRBN binder
    • Protein or peptide: Protein cereblon
    • Protein or peptide: DNA damage-binding protein 1
  • Ligand: ZINC ION
  • Ligand: (3R)-3-{1-methyl-6-[(piperidin-4-yl)amino]-1H-indazol-3-yl}piperidine-2,6-dione

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Supramolecule #1: CREBN-DDB1 plus a non-traditional CRBN binder

SupramoleculeName: CREBN-DDB1 plus a non-traditional CRBN binder / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: co-expressed in sf9 cells. beta-propeller domain of DDB1 replaced by a linker.
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.581984 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYYHHHHHH DYDIPTTGLV PRGSMMAGEG DQQDAAHNMG NHLPLLPAES EEEDEMEVED QDSKEAKKPN IINFDTSLPT SHTYLGADM EEFHGRTLHD DDSCQVIPVL PQVMMILIPG QTLPLQLFHP QEVSMVRNLI QKDRTFAVLA YSNVQEREAQ F GTTAEIYA ...String:
MSYYHHHHHH DYDIPTTGLV PRGSMMAGEG DQQDAAHNMG NHLPLLPAES EEEDEMEVED QDSKEAKKPN IINFDTSLPT SHTYLGADM EEFHGRTLHD DDSCQVIPVL PQVMMILIPG QTLPLQLFHP QEVSMVRNLI QKDRTFAVLA YSNVQEREAQ F GTTAEIYA YREEQDFGIE IVKVKAIGRQ RFKVLELRTQ SDGIQQAKVQ ILPECVLPST MSAVQLESLN KCQIFPSKPV SR EDQCSYK WWQKYQKRKF HCANLTSWPR WLYSLYDAET LMDRIKKQLR EWDENLKDDS LPSNPIDFSY RVAACLPIDD VLR IQLLKI GSAIQRLRCE LDIMNKCTSL CCKQCQETEI TTKNEIFSLS LCGPMAAYVN PHGYVHETLT VYKACNLNLI GRPS TEHSW FPGYAWTVAQ CKICASHIGW KFTATKKDMS PQKFWGLTRS ALLPTIPDTE DEISPDKVIL CL

UniProtKB: Protein cereblon

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Macromolecule #2: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.347078 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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, DNA damage-binding protein 1

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: (3R)-3-{1-methyl-6-[(piperidin-4-yl)amino]-1H-indazol-3-yl}piperi...

MacromoleculeName: (3R)-3-{1-methyl-6-[(piperidin-4-yl)amino]-1H-indazol-3-yl}piperidine-2,6-dione
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1BEP
Molecular weightTheoretical: 341.408 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

Concentration3.5 mg/mL
BufferpH: 7
Component:
ConcentrationFormulaName
10.0 mMHEPES(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethanesulfonic acid)
240.0 mMNaClsodium chloride
2.0 mMTCEPtris(2-carboxyethyl)phosphine
0.3 %DMSODimethyl sulfoxide
0.001 %LMNGLauryl Maltose Neopentyl Glycol
GridModel: Quantifoil R0.6/1 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recording#0 - Image recording ID: 1 / #0 - Film or detector model: FEI FALCON IV (4k x 4k) / #0 - Number grids imaged: 1 / #0 - Number real images: 11921 / #0 - Average exposure time: 3.03 sec. / #0 - Average electron dose: 27.67 e/Å2 / #1 - Image recording ID: 2 / #1 - Film or detector model: FEI FALCON IV (4k x 4k) / #1 - Number grids imaged: 1 / #1 - Number real images: 8200 / #1 - Average exposure time: 3.49 sec. / #1 - Average electron dose: 39.28 e/Å2 / #1 - Details: 30 degree tilt
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 75000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Image recording ID1
Particle selectionNumber selected: 7881094
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8d81

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 81146
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8d81


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9dqd:
cryo-EM structure of human Cereblon/DDB1 in complex with a non-traditional CRBN binder

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