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- PDB-9djx: Ternary complex structure of Cereblon-DDB1 bound to WIZ(ZF7) and ... -

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Basic information

Entry
Database: PDB / ID: 9djx
TitleTernary complex structure of Cereblon-DDB1 bound to WIZ(ZF7) and the molecular glue WIZ-6
Components
  • DNA damage-binding protein 1
  • Protein Wiz
  • Protein cereblon
KeywordsLIGASE / Cereblon / Molecular Glue / degradation
Function / homology
Function and homology information


positive regulation of nuclear cell cycle DNA replication / negative regulation of monoatomic ion transmembrane transport / histone methyltransferase binding / 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 ...positive regulation of nuclear cell cycle DNA replication / negative regulation of monoatomic ion transmembrane transport / histone methyltransferase binding / 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 / 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 / cullin family protein binding / viral release from host cell / 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 / Recognition of DNA damage by PCNA-containing replication complex / transcription corepressor binding / DNA Damage Recognition in GG-NER / nucleotide-excision repair / positive regulation of protein-containing complex assembly / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Formation of Incision Complex in GG-NER / regulation of circadian rhythm / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Wnt signaling pathway / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / site of double-strand break / Neddylation / midbody / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / DNA-binding transcription factor activity, RNA polymerase II-specific / chromosome, telomeric region / protein ubiquitination / protein stabilization / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA repair / apoptotic process / DNA damage response / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / protein-containing complex / extracellular space / DNA binding / extracellular exosome / zinc ion binding / nucleoplasm / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
: / : / Zinc finger found in WIZ protein / 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 ...: / : / Zinc finger found in WIZ protein / 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 / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
: / Protein Wiz / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.35 Å
AuthorsPartridge, J.R. / Ma, X. / Ornelas, E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease.
Authors: Kerrigan, J.R. / Thomsen, N.M. / Cernijenko, A. / Kochanek, S.E. / Dewhurst, J. / O'Brien, G. / Ware, N.F. / Sanchez, C.C. / Manning, J.R. / Ma, X. / Ornelas, E. / Savage, N.A. / Partridge, ...Authors: Kerrigan, J.R. / Thomsen, N.M. / Cernijenko, A. / Kochanek, S.E. / Dewhurst, J. / O'Brien, G. / Ware, N.F. / Sanchez, C.C. / Manning, J.R. / Ma, X. / Ornelas, E. / Savage, N.A. / Partridge, J.R. / Patterson, A.W. / Lam, P. / Dales, N.A. / Bonazzi, S. / Borikar, S. / Hinman, A.E. / Ting, P.Y.
History
DepositionSep 7, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)280,55715
Polymers279,2376
Non-polymers1,3219
Water39622
1
A: Protein cereblon
B: DNA damage-binding protein 1
C: Protein Wiz
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,2317
Polymers139,6183
Non-polymers6124
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5800 Å2
ΔGint-59 kcal/mol
Surface area47550 Å2
MethodPISA
2
D: Protein cereblon
E: DNA damage-binding protein 1
F: Protein Wiz
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,3278
Polymers139,6183
Non-polymers7085
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6170 Å2
ΔGint-71 kcal/mol
Surface area47300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.114, 145.029, 191.895
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 4 molecules ADBE

#1: Protein Protein cereblon


Mass: 42971.574 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2
#2: 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.: 2
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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Protein/peptide , 1 types, 2 molecules CF

#3: Protein/peptide Protein Wiz / Widely-interspaced zinc finger-containing protein / Zinc finger protein 803


Mass: 3299.722 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WIZ, ZNF803 / Production host: Escherichia coli (E. coli) / References: UniProt: O95785

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Non-polymers , 4 types, 31 molecules

#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-A1A5I / (3S)-3-(5-{[(3R,6S)-1-ethyl-6-methylpiperidin-3-yl]oxy}-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione


Mass: 385.457 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27N3O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.72 Å3/Da / Density % sol: 54.76 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.2 M Sodium Sulfate, 0.1M BIS-TRIS Propane pH 7.5, 20% PEG3350 (Qiagen PACT G8)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Apr 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.35→52.48 Å / Num. obs: 44026 / % possible obs: 98.7 % / Redundancy: 23.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.283 / Rpim(I) all: 0.059 / Rrim(I) all: 0.289 / Χ2: 1.01 / Net I/σ(I): 9.8 / Num. measured all: 1025053
Reflection shellResolution: 3.35→3.48 Å / % possible obs: 100 % / Redundancy: 17.8 % / Rmerge(I) obs: 4.452 / Num. measured all: 81974 / Num. unique obs: 4613 / CC1/2: 0.28 / Rpim(I) all: 1.077 / Rrim(I) all: 4.586 / Χ2: 1.04 / Net I/σ(I) obs: 0.8

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Processing

Software
NameVersionClassification
PHENIX(1.21_5207: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.35→46.88 Å / SU ML: 0.52 / Cross valid method: FREE R-VALUE / σ(F): 1.97 / Phase error: 29.75 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2709 2207 5.03 %
Rwork0.2022 --
obs0.2057 43910 98.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.35→46.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17543 0 75 22 17640
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00917990
X-RAY DIFFRACTIONf_angle_d1.04824513
X-RAY DIFFRACTIONf_dihedral_angle_d16.4576321
X-RAY DIFFRACTIONf_chiral_restr0.0552897
X-RAY DIFFRACTIONf_plane_restr0.0093154
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.35-3.420.39781700.3322576X-RAY DIFFRACTION100
3.42-3.50.34671280.31682609X-RAY DIFFRACTION100
3.5-3.590.36921440.28782585X-RAY DIFFRACTION100
3.59-3.690.3391260.2772376X-RAY DIFFRACTION90
3.69-3.80.30331200.24492604X-RAY DIFFRACTION100
3.8-3.920.33741290.25452346X-RAY DIFFRACTION90
3.92-4.060.31651320.22342620X-RAY DIFFRACTION100
4.06-4.220.30561270.19472643X-RAY DIFFRACTION100
4.22-4.410.22371120.16172646X-RAY DIFFRACTION100
4.41-4.640.23041140.16472633X-RAY DIFFRACTION100
4.64-4.940.23421410.16812645X-RAY DIFFRACTION100
4.94-5.320.27541450.17082619X-RAY DIFFRACTION100
5.32-5.850.2451560.18642653X-RAY DIFFRACTION100
5.85-6.690.27861440.19012670X-RAY DIFFRACTION100
6.69-8.420.24461760.20232675X-RAY DIFFRACTION100
8.42-46.880.23881430.18242803X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 27.8091 Å / Origin y: 10.6137 Å / Origin z: -20.868 Å
111213212223313233
T0.7947 Å2-0.0325 Å2-0.0532 Å2-0.9514 Å2-0.0062 Å2--0.9293 Å2
L0.1178 °2-0.2182 °20.0099 °2-0.6948 °20.0389 °2--0.2426 °2
S-0.0381 Å °0.0174 Å °0.0264 Å °-0.0356 Å °0.0659 Å °-0.0646 Å °0.0288 Å °-0.0107 Å °-0.0291 Å °
Refinement TLS groupSelection details: all

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