+Open data
-Basic information
Entry | Database: PDB / ID: 8d7z | ||||||
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Title | Cereblon-DDB1 bound to CC-92480 and Ikaros ZF1-2-3 | ||||||
Components |
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Keywords | LIGASE / Ubiquitin / CRL4 / Adaptor / Cereblon | ||||||
Function / homology | Function and homology information negative regulation of monoatomic ion transmembrane transport / lymphocyte differentiation / 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 ...negative regulation of monoatomic ion transmembrane transport / lymphocyte differentiation / 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 / NOTCH3 Intracellular Domain Regulates Transcription / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / locomotory exploration behavior / negative regulation of reproductive process / negative regulation of developmental process / cullin family protein binding / mesoderm development / positive regulation of Wnt signaling pathway / viral release from host cell / ectopic germ cell programmed cell death / positive regulation of viral genome replication / negative regulation of protein-containing complex assembly / pericentric heterochromatin / positive regulation of gluconeogenesis / erythrocyte differentiation / proteasomal protein catabolic process / Recognition of DNA damage by PCNA-containing replication complex / nucleotide-excision repair / positive regulation of protein-containing complex assembly / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / regulation of circadian rhythm / 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 / protein-macromolecule adaptor activity / site of double-strand break / Neddylation / chromatin organization / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / damaged DNA binding / chromosome, telomeric region / protein ubiquitination / cell cycle / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / DNA repair / negative regulation of DNA-templated transcription / apoptotic process / DNA damage response / protein-containing complex binding / nucleolus / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / perinuclear region of cytoplasm / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / membrane / identical protein binding / metal ion binding / nucleus / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å | ||||||
Authors | Watson, E.R. / Lander, G.C. | ||||||
Funding support | United States, 1items
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Citation | Journal: Science / Year: 2022 Title: Molecular glue CELMoD compounds are regulators of cereblon conformation. Authors: Edmond R Watson / Scott Novick / Mary E Matyskiela / Philip P Chamberlain / Andres H de la Peña / Jinyi Zhu / Eileen Tran / Patrick R Griffin / Ingrid E Wertz / Gabriel C Lander / Abstract: Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior ...Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo-electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)-CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8d7z.cif.gz | 270.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8d7z.ent.gz | 211 KB | Display | PDB format |
PDBx/mmJSON format | 8d7z.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/d7/8d7z ftp://data.pdbj.org/pub/pdb/validation_reports/d7/8d7z | HTTPS FTP |
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-Related structure data
Related structure data | 27240MC 8cvpC 8d7uC 8d7vC 8d7wC 8d7xC 8d7yC 8d80C 8d81C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 127097.469 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531 | ||||
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#2: Protein | Mass: 50603.676 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2 | ||||
#3: Protein | Mass: 9731.428 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: IKZF1, IK1, IKAROS, LYF1, ZNFN1A1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q13422 | ||||
#4: Chemical | #5: Chemical | ChemComp-QFC / | Has ligand of interest | Y | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Cereblon-DDB1 bound to CC-92480 and Ikaros / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT |
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Molecular weight | Value: 0.177 MDa / Experimental value: YES |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7 / Details: 20mM HEPES pH 7.0, 240mM NaCl, 3mM TCEP |
Specimen | Conc.: 20 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: HOMEMADE PLUNGER / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277 K / Details: Manual plunge in 4 degree C cold room |
-Electron microscopy imaging
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |
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Microscopy | Model: FEI TALOS ARCTICA |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 36000 X / Calibrated magnification: 43478 X / Nominal defocus max: 1200 nm / Nominal defocus min: 700 nm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 62.5 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.19.2_4158: / Classification: refinement | ||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 71540 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 49523 / Symmetry type: POINT | ||||||||||||||||||||||||
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