[English] 日本語
Yorodumi
- EMDB-27242: Cereblon~DDB1 bound to Pomalidomide -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-27242
TitleCereblon~DDB1 bound to Pomalidomide
Map data
Sample
  • Complex: Cereblon~DDB1 bound to Pomalidomide
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: S-Pomalidomide
KeywordsCRL4 / Ubiquitin / E3 / Cereblon / 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 / 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 ...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 / WD40-repeat domain binding / Cul4A-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 / proteasomal protein catabolic process / positive regulation of viral genome replication / positive regulation of gluconeogenesis / 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 / 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 / Neddylation / site of double-strand break / 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 repair / DNA damage response / protein-containing complex binding / negative regulation of apoptotic process / nucleolus / apoptotic process / perinuclear region of cytoplasm / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / membrane / nucleus / metal ion binding / 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) / Cleavage/polyadenylation specificity factor, A subunit, N-terminal ...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) / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / Mono-functional DNA-alkylating methyl methanesulfonate N-term / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / : / CPSF A subunit region / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsWatson ER / Lander GC
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
CitationJournal: 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
DepositionJun 7, 2022-
Header (metadata) releaseJul 20, 2022-
Map releaseJul 20, 2022-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_27242.png

Downloads & links

-
Map

FileDownload / File: emd_27242.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.91 Å/pix.
x 224 pix.
= 203.84 Å		0.91 Å/pix.
x 224 pix.
= 203.84 Å		0.91 Å/pix.
x 224 pix.
= 203.84 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.91 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.127
Minimum - Maximum-1.115006 - 1.5939943
Average (Standard dev.)-0.0013017611 (±0.042045847)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 203.84001 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Additional map: #1

Fileemd_27242_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #2

Fileemd_27242_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #1

Fileemd_27242_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : Cereblon~DDB1 bound to Pomalidomide

EntireName: Cereblon~DDB1 bound to Pomalidomide
Components
  • Complex: Cereblon~DDB1 bound to Pomalidomide
    • Protein or peptide: DNA damage-binding protein 1
    • Protein or peptide: Protein cereblon
  • Ligand: ZINC ION
  • Ligand: S-Pomalidomide

-
Supramolecule #1: Cereblon~DDB1 bound to Pomalidomide

SupramoleculeName: Cereblon~DDB1 bound to Pomalidomide / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 143 KDa

-
Macromolecule #1: DNA damage-binding protein 1

MacromoleculeName: DNA damage-binding protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.347078 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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 LRIIRNGIGG NGNS GEIQK LHIRTVPLYE SPRKICYQEV SQCFGVLSSR IEVQDTSGGT TALRPSASTQ ALSSSVSSSK LFSSSTAPHE TSFGE EVEV HNLLIIDQHT FEVLHAHQFL QNEYALSLVS CKLGKDPNTY FIVGTAMVYP EEAEPKQGRI VVFQYSDGKL QTVAEK EVK GAVYSMVEFN GKLLASINST VRLYEWTTEK ELRTECNHYN NIMALYLKTK GDFILVGDLM RSVLLLAYKP MEGNFEE IA RDFNPNWMSA VEILDDDNFL GAENAFNLFV CQKDSAATTD EERQHLQEVG LFHLGEFVNV FCHGSLVMQN LGETSTPT Q GSVLFGTVNG MIGLVTSLSE SWYNLLLDMQ NRLNKVIKSV GKIEHSFWRS FHTERKTEPA TGFIDGDLIE SFLDISRPK MQEVVANLQY DDGSGMKREA TADDLIKVVE ELTRIH

UniProtKB: DNA damage-binding protein 1, DNA damage-binding protein 1

-
Macromolecule #2: Protein cereblon

MacromoleculeName: Protein cereblon / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.603676 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

-
Macromolecule #4: S-Pomalidomide

MacromoleculeName: S-Pomalidomide / type: ligand / ID: 4 / Number of copies: 1 / Formula: Y70
Molecular weightTheoretical: 273.244 Da
Chemical component information

ChemComp-Y70:
S-Pomalidomide

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

Concentration20 mg/mL
BufferpH: 7 / Details: 20mM HEPES pH 7, 240mM NaCl, 3mM TCEP
GridModel: 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
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: HOMEMADE PLUNGER / Details: Manual plunge in 4 degree C cold room.

-
Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 62.5 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

+
Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 87327
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more