+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-27241 | |||||||||
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Title | Cereblon~DDB1 bound to Iberdomide and Ikaros ZF1-2-3 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Ubiquitin / CRL4 / Adaptor / Cereblon / LIGASE | |||||||||
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 / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / NOTCH3 Intracellular Domain Regulates Transcription ...negative regulation of monoatomic ion transmembrane transport / lymphocyte differentiation / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / NOTCH3 Intracellular Domain Regulates Transcription / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of reproductive process / negative regulation of developmental process / mesoderm development / locomotory exploration behavior / viral release from host cell / cullin family protein binding / ectopic germ cell programmed cell death / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / proteasomal protein catabolic process / positive regulation of viral genome replication / pericentric heterochromatin / positive regulation of gluconeogenesis / erythrocyte differentiation / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / positive regulation of protein-containing complex assembly / DNA Damage Recognition in GG-NER / regulation of circadian rhythm / 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 / cellular response to UV / rhythmic process / chromatin organization / site of double-strand break / Neddylation / protein-macromolecule adaptor activity / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / Potential therapeutics for SARS / damaged DNA binding / chromosome, telomeric region / protein ubiquitination / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / DNA repair / negative regulation of DNA-templated transcription / DNA damage response / protein-containing complex binding / negative regulation of apoptotic process / nucleolus / regulation of transcription by RNA polymerase II / apoptotic process / perinuclear region of cytoplasm / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / identical protein binding / membrane / nucleus / metal ion binding / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||
Authors | Watson ER / Lander GC | |||||||||
Funding support | United States, 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_27241.map.gz | 21.6 MB | EMDB map data format | |
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Header (meta data) | emd-27241-v30.xml emd-27241.xml | 23.1 KB 23.1 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_27241_fsc.xml | 7.4 KB | Display | FSC data file |
Images | emd_27241.png | 117 KB | ||
Filedesc metadata | emd-27241.cif.gz | 7.1 KB | ||
Others | emd_27241_additional_1.map.gz emd_27241_half_map_1.map.gz emd_27241_half_map_2.map.gz | 22.2 MB 39.8 MB 39.8 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-27241 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-27241 | HTTPS FTP |
-Validation report
Summary document | emd_27241_validation.pdf.gz | 875.2 KB | Display | EMDB validaton report |
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Full document | emd_27241_full_validation.pdf.gz | 874.8 KB | Display | |
Data in XML | emd_27241_validation.xml.gz | 15.1 KB | Display | |
Data in CIF | emd_27241_validation.cif.gz | 19.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27241 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-27241 | HTTPS FTP |
-Related structure data
Related structure data | 8d80MC 8cvpC 8d7uC 8d7vC 8d7wC 8d7xC 8d7yC 8d7zC 8d81C C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_27241.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.15 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: #1
File | emd_27241_additional_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_27241_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_27241_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Cereblon~DDB1 bound to Iberdomide and Ikaros ZF1-2-3
Entire | Name: Cereblon~DDB1 bound to Iberdomide and Ikaros ZF1-2-3 |
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Components |
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-Supramolecule #1: Cereblon~DDB1 bound to Iberdomide and Ikaros ZF1-2-3
Supramolecule | Name: Cereblon~DDB1 bound to Iberdomide and Ikaros ZF1-2-3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 177 KDa |
-Macromolecule #1: DNA damage-binding protein 1
Macromolecule | Name: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 127.097469 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: 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 LRIIRNGIGI HEHA SIDLP GIKGLWPLRS DPNRETDDTL VLSFVGQTRV LMLNGEEVEE TELMGFVDDQ QTFFCGNVAH QQLIQITSAS VRLVS QEPK ALVSEWKEPQ AKNISVASCN SSQVVVAVGR ALYYLQIHPQ ELRQISHTEM EHEVACLDIT PLGDSNGLSP LCAIGL WTD ISARILKLPS FELLHKEMLG GEIIPRSILM TTFESSHYLL CALGDGALFY FGLNIETGLL SDRKKVTLGT QPTVLRT FR SLSTTNVFAC SDRPTVIYSS NHKLVFSNVN LKEVNYMCPL NSDGYPDSLA LANNSTLTIG TIDEIQKLHI RTVPLYES P RKICYQEVSQ CFGVLSSRIE VQDTSGGTTA LRPSASTQAL SSSVSSSKLF SSSTAPHETS FGEEVEVHNL LIIDQHTFE VLHAHQFLQN EYALSLVSCK LGKDPNTYFI VGTAMVYPEE AEPKQGRIVV FQYSDGKLQT VAEKEVKGAV YSMVEFNGKL LASINSTVR LYEWTTEKEL RTECNHYNNI MALYLKTKGD FILVGDLMRS VLLLAYKPME GNFEEIARDF NPNWMSAVEI L DDDNFLGA ENAFNLFVCQ KDSAATTDEE RQHLQEVGLF HLGEFVNVFC HGSLVMQNLG ETSTPTQGSV LFGTVNGMIG LV TSLSESW YNLLLDMQNR LNKVIKSVGK IEHSFWRSFH TERKTEPATG FIDGDLIESF LDISRPKMQE VVANLQYDDG SGM KREATA DDLIKVVEEL TRIH UniProtKB: DNA damage-binding protein 1 |
-Macromolecule #2: Protein cereblon
Macromolecule | Name: Protein cereblon / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 50.603676 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MAGEGDQQDA AHNMGNHLPL LPAESEEEDE MEVEDQDSKE AKKPNIINFD TSLPTSHTYL GADMEEFHGR TLHDDDSCQV IPVLPQVMM ILIPGQTLPL QLFHPQEVSM VRNLIQKDRT FAVLAYSNVQ EREAQFGTTA EIYAYREEQD FGIEIVKVKA I GRQRFKVL ...String: MAGEGDQQDA AHNMGNHLPL LPAESEEEDE MEVEDQDSKE AKKPNIINFD TSLPTSHTYL GADMEEFHGR TLHDDDSCQV IPVLPQVMM ILIPGQTLPL QLFHPQEVSM VRNLIQKDRT FAVLAYSNVQ EREAQFGTTA EIYAYREEQD FGIEIVKVKA I GRQRFKVL ELRTQSDGIQ QAKVQILPEC VLPSTMSAVQ LESLNKCQIF PSKPVSREDQ CSYKWWQKYQ KRKFHCANLT SW PRWLYSL YDAETLMDRI KKQLREWDEN LKDDSLPSNP IDFSYRVAAC LPIDDVLRIQ LLKIGSAIQR LRCELDIMNK CTS LCCKQC QETEITTKNE IFSLSLCGPM AAYVNPHGYV HETLTVYKAC NLNLIGRPST EHSWFPGYAW TVAQCKICAS HIGW KFTAT KKDMSPQKFW GLTRSALLPT IPDTEDEISP DKVILCL UniProtKB: Protein cereblon |
-Macromolecule #3: DNA-binding protein Ikaros
Macromolecule | Name: DNA-binding protein Ikaros / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 9.731428 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: GSLPNGKLKC DICGIICIGP NVLMVHKRSH TGERPFQCNQ CGASFTQKGN LLRHIKLHSG EKPFKCHLCN YACRRRDALT GHLRTHS UniProtKB: DNA-binding protein Ikaros |
-Macromolecule #4: ZINC ION
Macromolecule | Name: ZINC ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: ZN |
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Molecular weight | Theoretical: 65.409 Da |
-Macromolecule #5: (3S)-3-[4-({4-[(morpholin-4-yl)methyl]phenyl}methoxy)-1-oxo-1,3-d...
Macromolecule | Name: (3S)-3-[4-({4-[(morpholin-4-yl)methyl]phenyl}methoxy)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione type: ligand / ID: 5 / Number of copies: 1 / Formula: 8W7 |
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Molecular weight | Theoretical: 449.499 Da |
Chemical component information | ChemComp-8W7: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 20 mg/mL |
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Buffer | pH: 7 / Details: 20mM HEPES pH 7.0, 240mM NaCl, 3mM TCEP |
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec. / Pretreatment - Atmosphere: OTHER |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277 K / Instrument: HOMEMADE PLUNGER / Details: Manual plunge in 4 degree C cold room. |
-Electron microscopy
Microscope | FEI TALOS ARCTICA |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 62.5 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Calibrated magnification: 43478 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 36000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |