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- PDB-8dey: Ternary complex structure of Cereblon-DDB1 bound to IKZF2(ZF2,3) ... -

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Basic information

Entry
Database: PDB / ID: 8dey
TitleTernary complex structure of Cereblon-DDB1 bound to IKZF2(ZF2,3) and the molecular glue DKY709
Components
  • DNA damage-binding protein 1
  • Protein cereblon
  • Zinc finger protein Helios
KeywordsLIGASE / E3 ligase / molecular glue / complex
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 / WD40-repeat domain binding / regulation of mitotic cell cycle phase transition / 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 / WD40-repeat domain binding / regulation of mitotic cell cycle phase transition / 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 / positive regulation of Wnt signaling pathway / viral release from host cell / ectopic germ cell programmed cell death / negative regulation of protein-containing complex assembly / positive regulation of viral genome replication / positive regulation of gluconeogenesis / proteasomal protein catabolic process / 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 / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / 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 / protein-macromolecule adaptor activity / site of double-strand break / Neddylation / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / Potential therapeutics for SARS / chromosome, telomeric region / damaged DNA binding / protein ubiquitination / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / DNA repair / apoptotic process / DNA damage response / protein-containing complex binding / nucleolus / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / perinuclear region of cytoplasm / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / membrane / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon protease, N-terminal domain superfamily / Lon N-terminal domain profile. / Lon protease, N-terminal domain / 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 protease, N-terminal domain superfamily / Lon N-terminal domain profile. / Lon protease, N-terminal domain / 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 / Zinc finger, C2H2 type / 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
Chem-LWK / DNA damage-binding protein 1 / Protein cereblon / Zinc finger protein Helios
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.7 Å
AuthorsMa, X. / Ornelas, E. / Clifton, M.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Chem Biol / Year: 2023
Title: Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy.
Authors: Bonazzi, S. / d'Hennezel, E. / Beckwith, R.E.J. / Xu, L. / Fazal, A. / Magracheva, A. / Ramesh, R. / Cernijenko, A. / Antonakos, B. / Bhang, H.C. / Caro, R.G. / Cobb, J.S. / Ornelas, E. / ...Authors: Bonazzi, S. / d'Hennezel, E. / Beckwith, R.E.J. / Xu, L. / Fazal, A. / Magracheva, A. / Ramesh, R. / Cernijenko, A. / Antonakos, B. / Bhang, H.C. / Caro, R.G. / Cobb, J.S. / Ornelas, E. / Ma, X. / Wartchow, C.A. / Clifton, M.C. / Forseth, R.R. / Fortnam, B.H. / Lu, H. / Csibi, A. / Tullai, J. / Carbonneau, S. / Thomsen, N.M. / Larrow, J. / Chie-Leon, B. / Hainzl, D. / Gu, Y. / Lu, D. / Meyer, M.J. / Alexander, D. / Kinyamu-Akunda, J. / Sabatos-Peyton, C.A. / Dales, N.A. / Zecri, F.J. / Jain, R.K. / Shulok, J. / Wang, Y.K. / Briner, K. / Porter, J.A. / Tallarico, J.A. / Engelman, J.A. / Dranoff, G. / Bradner, J.E. / Visser, M. / Solomon, J.M.
History
DepositionJun 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Mar 29, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3May 24, 2023Group: Refinement description / Structure summary / Category: audit_author / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.4Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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: Zinc finger protein Helios
D: Protein cereblon
E: DNA damage-binding protein 1
F: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)286,53413
Polymers285,7246
Non-polymers8107
Water0
1
A: Protein cereblon
B: DNA damage-binding protein 1
C: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,4767
Polymers142,8623
Non-polymers6144
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Protein cereblon
E: DNA damage-binding protein 1
F: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,0586
Polymers142,8623
Non-polymers1963
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)96.476, 96.227, 155.598
Angle α, β, γ (deg.)90.000, 93.460, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 71 through 110 or (resid 111...
21chain D
12(chain B and (resid 2 through 152 or (resid 153...
22(chain E and (resid 2 through 341 or (resid 342...
13chain C
23chain F

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111THRTHRVALVAL(chain A and (resid 71 through 110 or (resid 111...AA71 - 1102 - 41
121ARGARGARGARG(chain A and (resid 71 through 110 or (resid 111...AA11142
131THRTHRZNZN(chain A and (resid 71 through 110 or (resid 111...AA - G71 - 5012
141THRTHRZNZN(chain A and (resid 71 through 110 or (resid 111...AA - G71 - 5012
151THRTHRZNZN(chain A and (resid 71 through 110 or (resid 111...AA - G71 - 5012
161THRTHRZNZN(chain A and (resid 71 through 110 or (resid 111...AA - G71 - 5012
211THRTHRZNZNchain DDD - K71 - 5012
112SERSERLEULEU(chain B and (resid 2 through 152 or (resid 153...BB2 - 1522 - 152
122LYSLYSALAALA(chain B and (resid 2 through 152 or (resid 153...BB153 - 154153 - 154
132SERSERHISHIS(chain B and (resid 2 through 152 or (resid 153...BB2 - 11402 - 836
142SERSERHISHIS(chain B and (resid 2 through 152 or (resid 153...BB2 - 11402 - 836
152SERSERHISHIS(chain B and (resid 2 through 152 or (resid 153...BB2 - 11402 - 836
162SERSERHISHIS(chain B and (resid 2 through 152 or (resid 153...BB2 - 11402 - 836
212SERSERASNASN(chain E and (resid 2 through 341 or (resid 342...EE2 - 3412 - 341
222GLUGLUGLUGLU(chain E and (resid 2 through 341 or (resid 342...EE342342
232SERSERHISHIS(chain E and (resid 2 through 341 or (resid 342...EE2 - 11402 - 836
242SERSERHISHIS(chain E and (resid 2 through 341 or (resid 342...EE2 - 11402 - 836
252SERSERHISHIS(chain E and (resid 2 through 341 or (resid 342...EE2 - 11402 - 836
262SERSERHISHIS(chain E and (resid 2 through 341 or (resid 342...EE2 - 11402 - 836
113SERSERZNZNchain CCC - J136 - 2021
213SERSERZNZNchain FFF - M136 - 2021

NCS ensembles :
ID
1
2
3

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Components

#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, AD-006 / Production host: Escherichia coli (E. coli) / 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
Fragment: UNP residues 1-395,706-1140,UNP residues 1-395,706-1140
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q16531
#3: Protein Zinc finger protein Helios / / Ikaros family zinc finger protein 2


Mass: 6543.556 Da / Num. of mol.: 2 / Fragment: IKZF2 (UNP residues 137-192)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IKZF2, HELIOS, ZNFN1A2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UKS7
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-LWK / (3S)-3-[5-(1-benzylpiperidin-4-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione


Mass: 417.500 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27N3O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 2.52 Å3/Da / Density % sol: 51.25 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 1.6 M potassium/sodium phosphate, pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 22, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 3.7→84.15 Å / Num. obs: 30254 / % possible obs: 98.8 % / Redundancy: 5.035 % / Biso Wilson estimate: 124.56 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.151 / Rrim(I) all: 0.169 / Χ2: 0.776 / Net I/σ(I): 5.92 / Num. measured all: 152319 / Scaling rejects: 1418
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
3.7-3.85.2572.1080.7622150.3072.35299.9
3.8-3.94.8351.4651.320450.7121.6593
3.9-4.015.0822.2440.6520010.5582.51193.7
4.01-4.144.8751.0481.4420760.6581.17799.9
4.14-4.274.9990.7881.919790.7710.88299.9
4.27-4.425.0280.5023.0219450.8620.56299.8
4.42-4.595.3080.4053.6219170.9330.45100
4.59-4.785.2580.3464.217770.9480.38599.8
4.78-4.995.2320.2744.9717340.970.305100
4.99-5.235.1040.2745.0516800.9670.30699.9
5.23-5.524.8750.2395.7215620.9690.269100
5.52-5.854.9590.2116.4114970.9710.23799.8
5.85-6.255.3160.1987.2614070.9780.2299.9
6.25-6.765.2320.1379.7413300.9890.152100
6.76-7.45.0780.10811.8812180.990.1299.8
7.4-8.274.6180.08714.1610820.9920.09899.4
8.27-9.554.80.05918.999800.9950.06699.9
9.55-11.74.9340.0522.398300.9970.05699.9
11.7-16.554.3980.05121.46380.9960.05798
16.55-84.154.0970.05620.083410.9930.06490

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 7U8F

7u8f


Resolution: 3.7→84.15 Å / SU ML: 1.01 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 46.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.348 1501 5.07 %
Rwork0.2985 28123 -
obs0.3011 29624 96.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 289.32 Å2 / Biso mean: 155.5025 Å2 / Biso min: 64.63 Å2
Refinement stepCycle: final / Resolution: 3.7→84.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms19295 0 37 0 19332
Biso mean--172.56 --
Num. residues----2460
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2234X-RAY DIFFRACTION4.065TORSIONAL
12D2234X-RAY DIFFRACTION4.065TORSIONAL
21B4828X-RAY DIFFRACTION4.065TORSIONAL
22E4828X-RAY DIFFRACTION4.065TORSIONAL
31C348X-RAY DIFFRACTION4.065TORSIONAL
32F348X-RAY DIFFRACTION4.065TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.7-3.820.45091130.45932299241288
3.82-3.960.57791220.55622181230384
3.96-4.120.4361500.38882586273699
4.12-4.30.39981370.3622622275999
4.3-4.530.42451340.3226172751100
4.53-4.820.39081430.315126482791100
4.82-5.190.39971310.30732587271899
5.19-5.710.4071300.299526652795100
5.71-6.530.35311330.295126492782100
6.54-8.230.31821740.288326092783100
8.23-84.150.24241340.21132660279497

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