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- PDB-9svi: Cryo-EM structure of CRBN bound to 1-[1-(4-piperidyl)indol-4-yl]h... -

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Basic information

Entry
Database: PDB / ID: 9svi
TitleCryo-EM structure of CRBN bound to 1-[1-(4-piperidyl)indol-4-yl]hexahydropyrimidine-2,4-dione in the open conformation
Components
  • DNA damage-binding protein 1
  • Protein cereblon
KeywordsLIGASE / E3 ubiquitin 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 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 / nucleotide-excision repair complex / regulation of cell cycle phase transition / Cul4-RING E3 ubiquitin ligase complex / locomotory exploration behavior / regulation of stem cell population maintenance / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / Cul4B-RING E3 ubiquitin ligase complex / regulation of cellular response to stress / limb development / viral release from host cell / Cul4A-RING E3 ubiquitin ligase complex / 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 / regulation of embryonic development / replication fork processing / proteasomal protein catabolic process / 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 / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Dual Incision in GG-NER / Formation of Incision Complex in GG-NER / cellular response to UV / Dual incision in TC-NER / positive regulation of protein catabolic process / Gap-filling DNA repair synthesis and ligation in TC-NER / site of double-strand break / regulation of cell population proliferation / Neddylation / spermatogenesis / ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / damaged DNA binding / regulation of apoptotic process / transmembrane transporter binding / chromosome, telomeric region / protein-macromolecule adaptor activity / protein ubiquitination / DNA repair / DNA damage response / nucleolus / protein-containing complex binding / perinuclear region of cytoplasm / protein-containing complex / DNA binding / extracellular exosome / nucleoplasm / extracellular region / membrane / nucleus / 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) / : ...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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.33 Å
AuthorsCowan, A.D. / Rutter, Z.J. / McAulay, K. / Ciulli, A.
Funding support Germany, 1items
OrganizationGrant numberCountry
Boehringer Ingelheim Fonds (BIF) Germany
CitationJournal: To Be Published
Title: Structural and Biophysical Methods for the Assessment of Cereblon Binders for PROTACs
Authors: Rutter, Z.J. / Cowan, A.D. / McAulay, K. / Ciulli, A.
History
DepositionOct 3, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 14, 2026Provider: repository / Type: Initial release
Revision 1.0Oct 14, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)144,2844
Polymers143,9072
Non-polymers3782
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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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: 93347.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16531
#2: Protein Protein cereblon


Mass: 50559.559 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: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-A1JP8 / 1-(1-piperidin-4-ylindol-4-yl)-1,3-diazinane-2,4-dione


Mass: 312.366 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20N4O2 / 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: Complex of CRL4 E3 adapter-receptor pair DDB1 and CRBN bound to dihydrouracil ligand
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.14377612 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPES1
2200 mMsodium chlorideNaCl1
30.25 mMtris(2-carboxyethyl)phosphine1
40.011 %Lauryl Maltose-Neopentyl Glycol1
SpecimenConc.: 0.72 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: 35 mA / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 190000 X / Nominal defocus max: 3200 nm / Nominal defocus min: 1700 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2.35 sec. / Electron dose: 21.94 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3752

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6.2particle selection
4cryoSPARC4.6.2CTF correction
7UCSF ChimeraX1.9model fitting
8Coot0.9.8.95model fitting
10cryoSPARC4.6.2initial Euler assignment
11cryoSPARC4.7final Euler assignment
13cryoSPARC4.73D reconstruction
14PHENIX1.20.1-4487model refinement
CTF correctionDetails: Patch CTF / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.33 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 86485
Details: cryoSPARC non-uniform refinement was used for the final reconstruction of the consensus map, and cryoSPARC local refinement was used for the locally refined map of the thalidomide binding domain
Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Details: Initial fitting was done in ChimeraX, followed by flexible fitting in Coot. The model was refined with iterative rounds of building in Coot and refinement in PHENIX real space refine
Atomic model building
IDPDB-ID 3D fitting-IDDetails (eV)Source nameTypeAccession code
11Initial model for DDB1dBPB, CRBN LON and helical bundle was structure of CRBNmidi bound to spirocylic ligand in the open conformationOtherexperimental model
29SUN

9sun

1The initial model for the TBD and ligand were taken from the structure of CRBN midi in complex with the dihydrouracil ligandPDBexperimental model9SUN
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 51.39 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00359022
ELECTRON MICROSCOPYf_angle_d0.620112267
ELECTRON MICROSCOPYf_chiral_restr0.04621407
ELECTRON MICROSCOPYf_plane_restr0.00721597
ELECTRON MICROSCOPYf_dihedral_angle_d4.49831284

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