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- PDB-6bnb: Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET57 ... -

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Basic information

Entry
Database: PDB / ID: 6bnb
TitleCrystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET57 PROTAC
Components
  • Bromodomain-containing protein 4
  • 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 / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / 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 / Cul4-RING E3 ubiquitin ligase complex ...negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / 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 / Cul4-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 / RNA polymerase II C-terminal domain binding / cullin family protein binding / P-TEFb complex binding / viral release from host cell / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of Wnt signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / ectopic germ cell programmed cell death / positive regulation of T-helper 17 cell lineage commitment / negative regulation of protein-containing complex assembly / positive regulation of viral genome replication / proteasomal protein catabolic process / : / positive regulation of gluconeogenesis / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / nucleotide-excision repair / positive regulation of protein-containing complex assembly / positive regulation of transcription elongation by RNA polymerase II / Recognition of DNA damage by PCNA-containing replication complex / regulation of circadian rhythm / DNA Damage Recognition in GG-NER / 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 / Wnt signaling pathway / 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 / p53 binding / rhythmic process / site of double-strand break / chromosome / Neddylation / regulation of inflammatory response / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / histone binding / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / damaged DNA binding / transmembrane transporter binding / transcription coactivator activity / chromosome, telomeric region / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / protein ubiquitination / chromatin remodeling / DNA repair / protein serine/threonine kinase activity / apoptotic process / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / chromatin / positive regulation of DNA-templated transcription / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / extracellular space / DNA binding / extracellular exosome / nucleoplasm / metal ion binding / nucleus / membrane / cytoplasm / cytosol
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) / RSE1/DDB1/CPSF1 second beta-propeller ...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 / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
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: 6.343 Å
AuthorsNowak, R.P. / DeAngelo, S.L. / Buckley, D. / Ishoey, M. / He, Z. / Zhang, T. / 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
the 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 1.0May 30, 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 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id
Revision 1.5Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.6Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)164,8304
Polymers164,7653
Non-polymers651
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5960 Å2
ΔGint-29 kcal/mol
Surface area58460 Å2
Unit cell
Length a, b, c (Å)313.355, 313.355, 167.371
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422

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Components

#1: 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: 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 / Protein HUNK1


Mass: 15333.856 Da / Num. of mol.: 1 / Fragment: residues 42-168 / Mutation: T43M
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
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: 6.24 Å3/Da / Density % sol: 80.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 1.34M NaH2PO4, 0.33M K2HPO4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97241 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 19, 2017
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97241 Å / Relative weight: 1
ReflectionResolution: 6.34→156.68 Å / Num. obs: 8992 / % possible obs: 98.1 % / Redundancy: 25.4 % / CC1/2: 1 / Rmerge(I) obs: 0.165 / Rpim(I) all: 0.047 / Rrim(I) all: 0.172 / Net I/σ(I): 15.3
Reflection shellResolution: 6.34→7.08 Å / Redundancy: 26.2 % / Rmerge(I) obs: 2.952 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 2370 / CC1/2: 0.627 / Rpim(I) all: 0.815 / Rrim(I) all: 3.063 / % possible all: 93.4

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FQD chain A/B;3MXF chain A

5fqd

3mxf


Resolution: 6.343→147.632 Å / SU ML: 0.94 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 46.99 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.3805 415 4.63 %Random selection
Rwork0.3368 ---
obs0.3387 8964 98.19 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 6.343→147.632 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10026 0 1 0 10027
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01110246
X-RAY DIFFRACTIONf_angle_d1.47513891
X-RAY DIFFRACTIONf_dihedral_angle_d20.7073791
X-RAY DIFFRACTIONf_chiral_restr0.0811575
X-RAY DIFFRACTIONf_plane_restr0.0041785
LS refinement shellResolution: 6.343→6.57 Å
RfactorNum. reflection
Rfree0.511 28
Rwork0.4151 -
obs-743

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