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

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Basic information

Entry
Database: PDB / ID: 9djt
TitleTernary complex structure of Cereblon-DDB1 bound to WIZ(ZF7) and the molecular glue WIZ-5
Components
  • DNA damage-binding protein 1
  • Protein Wiz
  • Protein cereblon
KeywordsLIGASE / Cereblon / Molecular Glue
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: 2.95 Å
AuthorsPartridge, J.R. / Ma, X. / Ornelas, E.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: 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.
#1: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionSep 6, 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)280,48514
Polymers279,2376
Non-polymers1,2498
Water75742
1
A: Protein cereblon
B: DNA damage-binding protein 1
C: Protein Wiz
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,2437
Polymers139,6183
Non-polymers6244
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5830 Å2
ΔGint-60 kcal/mol
Surface area48430 Å2
MethodPISA
2
D: Protein cereblon
E: DNA damage-binding protein 1
F: Protein Wiz
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,2437
Polymers139,6183
Non-polymers6244
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5940 Å2
ΔGint-61 kcal/mol
Surface area48150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.711, 145.600, 192.099
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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, 50 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.: 2 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-A1A5H / (3S)-3-(5-{[(4R)-6-ethyl-6-azaspiro[2.5]octan-4-yl]oxy}-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione


Mass: 397.467 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H27N3O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 42 / 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: 2.75 Å3/Da / Density % sol: 55.23 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.2 M Sodium Sulfate, 0.1 M Bis-Tris Propane pH 7.5, 20% w/v PEG 3350

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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: 2.95→29.96 Å / Num. obs: 64947 / % possible obs: 99.3 % / Redundancy: 13.9 % / Biso Wilson estimate: 97.55 Å2 / CC1/2: 0.998 / Rsym value: 0.227 / Net I/σ(I): 8.9
Reflection shellResolution: 2.95→3.02 Å / Redundancy: 14 % / Num. unique obs: 4489 / CC1/2: 0.303 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.95→29.96 Å / SU ML: 0.48 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 31.59 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.26 3177 4.91 %
Rwork0.2051 --
obs0.2079 64731 99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.95→29.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17574 0 72 42 17688
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00918029
X-RAY DIFFRACTIONf_angle_d1.07424570
X-RAY DIFFRACTIONf_dihedral_angle_d20.4416330
X-RAY DIFFRACTIONf_chiral_restr0.0522897
X-RAY DIFFRACTIONf_plane_restr0.0083163
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.95-2.990.40791060.38912626X-RAY DIFFRACTION98
2.99-3.040.34561460.34692622X-RAY DIFFRACTION98
3.04-3.090.34631330.32352613X-RAY DIFFRACTION99
3.09-3.140.37841210.32062662X-RAY DIFFRACTION99
3.14-3.20.35651430.31462613X-RAY DIFFRACTION99
3.2-3.260.38341260.30282663X-RAY DIFFRACTION99
3.26-3.330.34421210.29852655X-RAY DIFFRACTION99
3.33-3.40.37611390.28962649X-RAY DIFFRACTION99
3.4-3.480.35511540.2672625X-RAY DIFFRACTION99
3.48-3.570.31591390.2432640X-RAY DIFFRACTION99
3.57-3.660.29561600.2222655X-RAY DIFFRACTION99
3.66-3.770.30231210.21672652X-RAY DIFFRACTION99
3.77-3.890.29031190.21752708X-RAY DIFFRACTION99
3.89-4.030.25021390.19422646X-RAY DIFFRACTION99
4.03-4.190.26451430.18942664X-RAY DIFFRACTION99
4.19-4.380.25211620.16932678X-RAY DIFFRACTION99
4.38-4.610.20371460.16682677X-RAY DIFFRACTION99
4.61-4.90.21831380.1572700X-RAY DIFFRACTION100
4.9-5.280.23721380.17232707X-RAY DIFFRACTION99
5.28-5.80.26991500.18682720X-RAY DIFFRACTION100
5.8-6.640.25031350.19972740X-RAY DIFFRACTION100
6.64-8.330.25481530.19992770X-RAY DIFFRACTION100
8.33-29.960.19341450.17692869X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 27.7128 Å / Origin y: 10.8362 Å / Origin z: -20.4147 Å
111213212223313233
T0.6905 Å2-0.0644 Å2-0.0835 Å2-0.8674 Å2-0.0033 Å2--0.7978 Å2
L0.1479 °2-0.2787 °2-0.003 °2-0.7531 °20.0346 °2--0.2907 °2
S-0.0344 Å °0.0227 Å °0.0326 Å °-0.0547 Å °0.0538 Å °-0.0596 Å °0.0249 Å °-0.0085 Å °-0.0181 Å °
Refinement TLS groupSelection details: all

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