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

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Basic information

Entry
Database: PDB / ID: 9hpi
TitleCryo-EM structure of DDB1dB-CRBN-MRT-0031619, conformation 1
Components
  • DNA damage-binding protein 1
  • Protein cereblon
KeywordsLIGASE / Targeted protein degradation / molecular glue / ubiquitin proteasome system / CRBN / 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 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.93 Å
AuthorsLangousis, G. / Hunkeler, M. / Chami, M. / Quan, C. / Townson, S. / Bonenfant, D.
Funding support1items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 3, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA damage-binding protein 1
B: Protein cereblon
C: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)186,9497
Polymers185,8453
Non-polymers1,1044
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, assembly revealed in cryo-EM and SEC-MALS
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 / Mutation: aa396-705 replaced with GNGNSG
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: 46249.180 Da / Num. of mol.: 2
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.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-A1IW1 / (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


Mass: 486.562 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H30N4O4 / 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: Drug-induced ternary complex between two DDB1-CRBN moieties
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.287 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
Details: Sample supplemented with DDM directly before vitrification
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPEShepes1
2100 mMsodium chloridenacl1
30.5 mMTCEPTCEP1
40.01 %DDMDDM1
SpecimenConc.: 9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 283 K / Details: LEICA EMGP2

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS / Details: collected with AFIS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 20 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 20582 / Details: Movies with 52 frames
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1Topaz0.2.5particle selection
2EPU3.8.1image acquisition
4CTFFIND4.1.10CTF correction
5RELION5CTF correction
8UCSF ChimeraX1.8model fitting
9ISOLDE1.8model fitting
11RELION5initial Euler assignment
12RELION5final Euler assignment
13RELION5classification
14RELION53D reconstruction
15PHENIX1.21model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4802227 / Details: TOPAZ with general model
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 203344 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingB value: 73 / Protocol: OTHER / Space: REAL / Target criteria: real space cross correlation / Details: real space refinement in COOT and phenix
Atomic model buildingPDB-ID: 8TNQ

8tnq


Accession code: 8TNQ / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.93 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312339
ELECTRON MICROSCOPYf_angle_d0.5116708
ELECTRON MICROSCOPYf_dihedral_angle_d5.2021695
ELECTRON MICROSCOPYf_chiral_restr0.0441878
ELECTRON MICROSCOPYf_plane_restr0.0042147

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