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Yorodumi- PDB-8d7y: Cereblon-DDB1 in the Apo form with DDB1 in the twisted conformation -
+Open data
-Basic information
Entry | Database: PDB / ID: 8d7y | ||||||
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Title | Cereblon-DDB1 in the Apo form with DDB1 in the twisted conformation | ||||||
Components |
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Keywords | LIGASE / Ubiquitin / CRL4 / Adaptor / Cereblon | ||||||
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 / Cul4A-RING E3 ubiquitin ligase complex / WD40-repeat domain binding ...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 / Cul4A-RING E3 ubiquitin ligase complex / WD40-repeat domain binding / ubiquitin ligase complex scaffold activity / Cul4B-RING E3 ubiquitin ligase complex / 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 / proteasomal protein catabolic process / negative regulation of protein-containing complex assembly / positive regulation of viral genome replication / positive regulation of gluconeogenesis / regulation of circadian rhythm / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / positive regulation of protein-containing complex assembly / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Dual Incision in GG-NER / 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 / rhythmic process / cellular response to UV / Neddylation / protein-macromolecule adaptor activity / site of double-strand break / chromosome, telomeric region / ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / damaged DNA binding / protein ubiquitination / DNA repair / DNA damage response / negative regulation of apoptotic process / protein-containing complex binding / nucleolus / apoptotic process / perinuclear region of cytoplasm / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / membrane / nucleus / metal ion binding / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 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. #1: Journal: Biorxiv / Year: 2022 Title: Molecular glue CELMoD compounds are allosteric regulators of cereblon conformation Authors: Watson, E.R. / Novick, S.J. / Matyskiela, M.E. / Chamberlain, P.P. / de la Pena, A.H. / Zhu, J.Y. / Tran, E. / Griffin, P.R. / Wertz, I.E. / Lander, G.C. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8d7y.cif.gz | 253.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8d7y.ent.gz | 189.8 KB | Display | PDB format |
PDBx/mmJSON format | 8d7y.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8d7y_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 8d7y_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 8d7y_validation.xml.gz | 50.9 KB | Display | |
Data in CIF | 8d7y_validation.cif.gz | 76.9 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/d7/8d7y ftp://data.pdbj.org/pub/pdb/validation_reports/d7/8d7y | HTTPS FTP |
-Related structure data
Related structure data | 27238MC 8cvpC 8d7uC 8d7vC 8d7wC 8d7xC 8d7zC 8d80C 8d81C C: citing same article (ref.) M: map data used to model this data |
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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: Chemical | ChemComp-ZN / |
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 in the Apo form with DDB1 in Twisted conformation Type: COMPLEX / Entity ID: #1-#2 / 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 FIELD / 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 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 32181 / Symmetry type: POINT | ||||||||||||||||||||||||
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