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- PDB-6bn7: Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET23 ... -

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Basic information

Entry
Database: PDB / ID: 6bn7
TitleCrystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET23 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 large conductance calcium-activated potassium channel activity / 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 large conductance calcium-activated potassium channel activity / 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 / negative regulation of reproductive process / negative regulation of developmental process / locomotory exploration behavior / cullin family protein binding / viral release from host cell / RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / positive regulation of Wnt signaling pathway / negative regulation by host of viral transcription / ectopic germ cell programmed cell death / negative regulation of protein-containing complex assembly / positive regulation of viral genome replication / positive regulation of T-helper 17 cell lineage commitment / proteasomal protein catabolic process / positive regulation of gluconeogenesis / positive regulation of G2/M transition of mitotic cell cycle / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader activity / condensed nuclear chromosome / nucleotide-excision repair / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / positive regulation of protein-containing complex assembly / lysine-acetylated histone binding / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / regulation of circadian rhythm / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Dual Incision in GG-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 / p53 binding / rhythmic process / Neddylation / chromosome / site of double-strand break / ubiquitin-dependent protein catabolic process / regulation of inflammatory response / protein-macromolecule adaptor activity / positive regulation of canonical NF-kappaB signal transduction / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / Potential therapeutics for SARS / damaged DNA binding / transcription coactivator activity / chromosome, telomeric region / transcription cis-regulatory region binding / protein ubiquitination / chromatin remodeling / DNA repair / DNA damage response / chromatin binding / apoptotic process / regulation of transcription by RNA polymerase II / protein-containing complex binding / negative regulation of apoptotic process / nucleolus / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / nucleus / membrane / metal ion binding / 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 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) / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / RSE1/DDB1/CPSF1 first beta-propeller / 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 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / YVTN repeat-like/Quinoprotein amine dehydrogenase / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Beta Complex / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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
Chem-RN3 / 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: 3.501 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
the Friends of Dana Farber United States
Claudia Adams Barr Program for Innovative Cancer Research United States
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 1.3Feb 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
B: Protein cereblon
C: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,4815
Polymers164,5303
Non-polymers9512
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6500 Å2
ΔGint-38 kcal/mol
Surface area55820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.571, 115.571, 596.315
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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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: 15099.380 Da / Num. of mol.: 1 / 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
#5: Chemical ChemComp-RN3 / methyl {(6S)-4-(4-chlorophenyl)-2-[(8-{[({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetyl]amino}octyl)carbamoyl]-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate


Mass: 885.384 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C43H45ClN8O9S / Feature type: SUBJECT OF INVESTIGATION

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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: 3.71 Å3/Da / Density % sol: 66.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 9% (w/v) PEG20K, 18% (v/v) PEG MME 550, 0.09M BICINE pH8.5, 9% Silver bullet B5 (0.33% w/v 2,7-Naphthalenedisulfonic acid disodium salt, 0.33% w/v Azelaic acid, 0.33% w/v trans-Cinnamic ...Details: 9% (w/v) PEG20K, 18% (v/v) PEG MME 550, 0.09M BICINE pH8.5, 9% Silver bullet B5 (0.33% w/v 2,7-Naphthalenedisulfonic acid disodium salt, 0.33% w/v Azelaic acid, 0.33% w/v trans-Cinnamic 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: 0.9791 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 20, 2016
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 3.49→49.87 Å / Num. obs: 31460 / % possible obs: 99.5 % / Redundancy: 11.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.128 / Rpim(I) all: 0.055 / Rrim(I) all: 0.14 / Net I/σ(I): 11.4
Reflection shellResolution: 3.49→3.68 Å / Redundancy: 10.5 % / Rmerge(I) obs: 3.561 / Mean I/σ(I) obs: 0.7 / Num. unique obs: 4335 / CC1/2: 0.328 / Rpim(I) all: 1.173 / Rrim(I) all: 3.924 / % possible all: 97.3

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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: 3mxf, 5fqd

3mxf

5fqd


Resolution: 3.501→49.868 Å / SU ML: 0.55 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 27.83
RfactorNum. reflection% reflectionSelection details
Rfree0.2555 1454 4.78 %Random selection
Rwork0.2123 ---
obs0.2143 30441 97.87 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.501→49.868 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10268 0 63 0 10331
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00710550
X-RAY DIFFRACTIONf_angle_d0.48114318
X-RAY DIFFRACTIONf_dihedral_angle_d14.9563917
X-RAY DIFFRACTIONf_chiral_restr0.0421616
X-RAY DIFFRACTIONf_plane_restr0.0031884
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.5007-3.62580.38561430.35612515X-RAY DIFFRACTION88
3.6258-3.77090.37571360.36182686X-RAY DIFFRACTION94
3.7709-3.94240.41581450.34972769X-RAY DIFFRACTION96
3.9424-4.15020.31491480.25692911X-RAY DIFFRACTION100
4.1502-4.41010.22821280.18852929X-RAY DIFFRACTION100
4.4101-4.75030.20461520.15682915X-RAY DIFFRACTION100
4.7503-5.22790.1961530.17142951X-RAY DIFFRACTION100
5.2279-5.98330.2571480.20372978X-RAY DIFFRACTION100
5.9833-7.53420.26521550.23163032X-RAY DIFFRACTION100
7.5342-49.87340.24671460.19963301X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 67.9938 Å / Origin y: 54.2194 Å / Origin z: 8.302 Å
111213212223313233
T0.7833 Å20.0492 Å2-0.0541 Å2-1.8902 Å20.4188 Å2--1.5223 Å2
L1.0339 °20.5779 °2-0.5427 °2-0.8984 °2-0.4141 °2--2.0829 °2
S-0.113 Å °0.5012 Å °0.2388 Å °0.065 Å °0.1168 Å °0.1213 Å °-0.2555 Å °0.3313 Å °0.0254 Å °
Refinement TLS groupSelection details: all

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