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- PDB-6bn8: Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET55 ... -

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Basic information

Entry
Database: PDB / ID: 6bn8
TitleCrystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET55 PROTAC.
Components
  • Bromodomain-containing protein 4BRD4
  • DNA damage-binding protein 1,DNA damage-binding protein 1
  • Protein cereblon
KeywordsLIGASE / PROTAC / degrader / E3 ligase / CRBN
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 / locomotory exploration behavior / negative regulation of reproductive process / negative regulation of developmental process / cullin family protein binding / RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / positive regulation of Wnt signaling pathway / P-TEFb complex binding / viral release from host cell / negative regulation by host of viral transcription / ectopic germ cell programmed cell death / positive regulation of viral genome replication / negative regulation of protein-containing complex assembly / positive regulation of gluconeogenesis / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / proteasomal protein catabolic process / Recognition of DNA damage by PCNA-containing replication complex / nucleotide-excision repair / positive regulation of protein-containing complex assembly / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / DNA Damage Recognition in GG-NER / lysine-acetylated histone binding / Dual Incision in GG-NER / regulation of circadian rhythm / 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 / cellular response to UV / rhythmic process / protein-macromolecule adaptor activity / p53 binding / site of double-strand break / chromosome / Neddylation / regulation of inflammatory response / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / transmembrane transporter binding / damaged DNA binding / chromosome, telomeric region / transcription coactivator activity / protein ubiquitination / transcription cis-regulatory region binding / chromatin remodeling / DNA repair / apoptotic process / DNA damage response / chromatin binding / protein-containing complex binding / nucleolus / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / perinuclear region of cytoplasm / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / membrane / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1480 / LON domain-like / Peptide methionine sulfoxide reductase. / DNA polymerase; domain 1 - #910 / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / Metal Binding Protein, Guanine Nucleotide Exchange Factor; Chain A / Archaeosine Trna-guanine Transglycosylase; Chain: A, domain 4 / CULT domain / CULT domain profile. ...Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1480 / LON domain-like / Peptide methionine sulfoxide reductase. / DNA polymerase; domain 1 - #910 / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / Metal Binding Protein, Guanine Nucleotide Exchange Factor; Chain A / Archaeosine Trna-guanine Transglycosylase; Chain: A, domain 4 / 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 / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / YVTN repeat-like/Quinoprotein amine dehydrogenase / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / 7 Propeller / Methylamine Dehydrogenase; Chain H / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Beta Complex / Bromodomain-like / Histone Acetyltransferase; Chain A / DNA polymerase; domain 1 / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Roll / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Up-down Bundle / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Bromodomain-containing protein 4 / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.99003499985 Å
AuthorsNowak, R.P. / DeAngelo, S.L. / Buckley, D. / Bradner, J.E. / Fischer, E.S.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)NCI R01CA214608 United States
The Harvard University William F. Milton Fund United States
Friends of Dana Farber United States
the Claudia Adams Barr Program for Innovative Cancer Research United States
the Linde Family Foundation United States
CitationJournal: Nat. Chem. Biol. / Year: 2018
Title: Plasticity in binding confers selectivity in ligand-induced protein degradation.
Authors: Nowak, R.P. / DeAngelo, S.L. / Buckley, D. / He, Z. / Donovan, K.A. / An, J. / Safaee, N. / Jedrychowski, M.P. / Ponthier, C.M. / Ishoey, M. / Zhang, T. / Mancias, J.D. / Gray, N.S. / ...Authors: Nowak, R.P. / DeAngelo, S.L. / Buckley, D. / He, Z. / Donovan, K.A. / An, J. / Safaee, N. / Jedrychowski, M.P. / Ponthier, C.M. / Ishoey, M. / Zhang, T. / Mancias, J.D. / Gray, N.S. / Bradner, J.E. / Fischer, E.S.
History
DepositionNov 16, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 6, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 1, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 7, 2018Group: Data collection / 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
Revision 1.3Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA damage-binding protein 1,DNA damage-binding protein 1
B: Protein cereblon
C: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)164,5524
Polymers164,4863
Non-polymers651
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5680 Å2
ΔGint-37 kcal/mol
Surface area56360 Å2
Unit cell
Length a, b, c (Å)115.204, 115.204, 597.135
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Space group name HallP652(x,y,z+1/12)

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Components

#1: Protein DNA damage-binding protein 1,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: 96425.586 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16531
#2: Protein Protein cereblon


Mass: 53005.207 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96SW2
#3: Protein Bromodomain-containing protein 4 / BRD4 / Protein HUNK1


Mass: 15055.370 Da / Num. of mol.: 1 / Mutation: T43M, D145A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn

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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: 3.48 Å3/Da / Density % sol: 64.63 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 9% PEG20K, 18% PEG MME 550, 0.09M BICINE pH8.5, 9% Silver bullet G4 (0.16% w/v 3-Indolebutyric acid, 0.16% w/v Hexadecanedioic acid, 0.16% w/v Oxamic acid, 0.16% w/v Pyromellitic acid, 0.16% ...Details: 9% PEG20K, 18% PEG MME 550, 0.09M BICINE pH8.5, 9% Silver bullet G4 (0.16% w/v 3-Indolebutyric acid, 0.16% w/v Hexadecanedioic acid, 0.16% w/v Oxamic acid, 0.16% w/v Pyromellitic acid, 0.16% w/v Sebacic acid, 0.16% w/v Suberic acid, 0.02 M HEPES sodium pH 6.8)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97919 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 15, 2017
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97919 Å / Relative weight: 1
ReflectionResolution: 3.99→149.28 Å / Num. obs: 21315 / % possible obs: 100 % / Redundancy: 17 % / Biso Wilson estimate: 171.90188794 Å2 / CC1/2: 0.991 / Rmerge(I) obs: 0.28 / Rpim(I) all: 0.096 / Rrim(I) all: 0.296 / Net I/σ(I): 7.9
Reflection shellResolution: 3.99→4.31 Å / Redundancy: 16.1 % / Rmerge(I) obs: 2.227 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 4219 / CC1/2: 0.452 / Rpim(I) all: 0.799 / Rrim(I) all: 2.367 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6BN7

6bn7


Resolution: 3.99003499985→99.769592696 Å / SU ML: 0.698541051771 / Cross valid method: FREE R-VALUE / σ(F): 1.3474641205 / Phase error: 33.6089833322
RfactorNum. reflection% reflectionSelection details
Rfree0.333448911462 1079 5.09130373236 %Random selection
Rwork0.288604646472 ---
obs0.290770625804 21193 99.9528368627 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 189.695887993 Å2
Refinement stepCycle: LAST / Resolution: 3.99003499985→99.769592696 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10290 0 1 0 10291
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0016251312879910505
X-RAY DIFFRACTIONf_angle_d0.45838254045814256
X-RAY DIFFRACTIONf_chiral_restr0.04186569175621617
X-RAY DIFFRACTIONf_plane_restr0.003857331058111838
X-RAY DIFFRACTIONf_dihedral_angle_d3.12602789036328
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.99-4.17160.4083847316391190.3753561675582421X-RAY DIFFRACTION99.725166863
4.1716-4.39160.3721750151351350.3631784642052426X-RAY DIFFRACTION100
4.3916-4.66670.3752042132581500.3359129827172438X-RAY DIFFRACTION100
4.6667-5.0270.370075718811410.3220265858642461X-RAY DIFFRACTION99.9615827891
5.027-5.53290.3182048698151320.3229878654852495X-RAY DIFFRACTION100
5.5329-6.33340.3968307106661240.3305680073162509X-RAY DIFFRACTION100
6.3334-7.97890.3511342744161490.2933069576812559X-RAY DIFFRACTION100
7.9789-99.80070.271713968911290.2290592298662805X-RAY DIFFRACTION99.931880109

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