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- PDB-6g0s: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 6g0s
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with an acetylated SIRT7 peptide (K272ac/K275ac)
Components
  • Bromodomain-containing protein 4
  • NAD-dependent protein deacetylase sirtuin-7
KeywordsTRANSCRIPTION / Bromodomain / complex
Function / homology
Function and homology information


regulation of transcription of nucleolar large rRNA by RNA polymerase I / nucleolus organizer region / protein depropionylation / NAD-dependent protein-lysine depropionylase activity / protein deglutarylation / protein-glutaryllysine deglutarylase activity / histone H3K18 deacetylase activity, NAD-dependent / protein-succinyllysine desuccinylase activity / R-loop processing / homologous chromosome pairing at meiosis ...regulation of transcription of nucleolar large rRNA by RNA polymerase I / nucleolus organizer region / protein depropionylation / NAD-dependent protein-lysine depropionylase activity / protein deglutarylation / protein-glutaryllysine deglutarylase activity / histone H3K18 deacetylase activity, NAD-dependent / protein-succinyllysine desuccinylase activity / R-loop processing / homologous chromosome pairing at meiosis / protein methyltransferase activity / transposable element silencing / NAD-dependent protein lysine deacetylase activity / protein acetyllysine N-acetyltransferase / positive regulation of rRNA processing / regulation of protein export from nucleus / protein deacetylation / regulation of mitochondrion organization / DNA repair-dependent chromatin remodeling / positive regulation of transcription by RNA polymerase I / RNA polymerase II C-terminal domain binding / P-TEFb complex binding / rRNA transcription / negative regulation of DNA damage checkpoint / histone H4 reader activity / NAD+ binding / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / regulation of DNA repair / : / negative regulation of protein ubiquitination / positive regulation of gluconeogenesis / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / RNA polymerase II CTD heptapeptide repeat kinase activity / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / transcription initiation-coupled chromatin remodeling / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / osteoblast differentiation / p53 binding / site of double-strand break / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / transcription coactivator activity / hydrolase activity / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / nuclear speck / chromatin remodeling / DNA repair / protein serine/threonine kinase activity / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / positive regulation of DNA-templated transcription / nucleolus / enzyme binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / nucleoplasm / metal ion binding / nucleus / cytoplasm
Similarity search - Function
Sirtuin family / : / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / DHS-like NAD/FAD-binding domain superfamily / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II ...Sirtuin family / : / Sir2 family / Sirtuin family, catalytic core domain / Sirtuin catalytic domain profile. / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / DHS-like NAD/FAD-binding domain superfamily / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Bromodomain-containing protein 4 / NAD-dependent protein deacetylase sirtuin-7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.48 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Krojer, T. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust095751/Z/11/Z United Kingdom
CitationJournal: Mol Cell / Year: 2019
Title: Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.
Authors: Jean-Philippe Lambert / Sarah Picaud / Takao Fujisawa / Huayun Hou / Pavel Savitsky / Liis Uusküla-Reimand / Gagan D Gupta / Hala Abdouni / Zhen-Yuan Lin / Monika Tucholska / James D R ...Authors: Jean-Philippe Lambert / Sarah Picaud / Takao Fujisawa / Huayun Hou / Pavel Savitsky / Liis Uusküla-Reimand / Gagan D Gupta / Hala Abdouni / Zhen-Yuan Lin / Monika Tucholska / James D R Knight / Beatriz Gonzalez-Badillo / Nicole St-Denis / Joseph A Newman / Manuel Stucki / Laurence Pelletier / Nuno Bandeira / Michael D Wilson / Panagis Filippakopoulos / Anne-Claude Gingras /
Abstract: Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, ...Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, BRD3, BRD4, and BRDT following treatment with the pan-BET BRD inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behavior for the 603 unique interactors identified. A group of proteins associate in a JQ1-sensitive manner with BET BRDs through canonical and new binding modes, while two classes of extra-terminal (ET)-domain binding motifs mediate acetylation-independent interactions. Last, we identify an unexpected increase in several interactions following JQ1 treatment that define negative functions for BRD3 in the regulation of rRNA synthesis and potentially RNAPII-dependent gene expression that result in decreased cell proliferation. Together, our data highlight the contributions of BET protein modules to their interactomes allowing for a better understanding of pharmacological rewiring in response to JQ1.
History
DepositionMar 19, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 28, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 26, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 20, 2019Group: Data collection / Database references
Category: citation / database_PDB_rev ...citation / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc / pdbx_struct_ref_seq_depositor_info
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _pdbx_struct_ref_seq_depositor_info.db_seq_one_letter_code
Revision 1.3Jan 17, 2024Group: 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
Revision 1.4Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
D: NAD-dependent protein deacetylase sirtuin-7
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,7966
Polymers31,6093
Non-polymers1863
Water4,414245
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3210 Å2
ΔGint-13 kcal/mol
Surface area14340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.393, 59.376, 106.017
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 15099.380 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): R3 / References: UniProt: O60885
#2: Protein/peptide NAD-dependent protein deacetylase sirtuin-7 / Regulatory protein SIR2 homolog 7 / SIR2-like protein 7


Mass: 1410.677 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: SIRT7 peptide acetylated at K272 and K275 C-terminal TYR added for UV detection
Source: (synth.) Homo sapiens (human)
References: UniProt: Q9NRC8, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 245 / Source method: isolated from a natural source / Formula: H2O
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: 2.12 Å3/Da / Density % sol: 41.88 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 20.0 % PEG3350 10.0 % EtGly 0.1 M bis-tris-propane pH 8.5 0.2M NaOOCCH3

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 28, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.475→51.805 Å / Num. all: 45984 / Num. obs: 45984 / % possible obs: 100 % / Redundancy: 7.2 % / Rpim(I) all: 0.031 / Rrim(I) all: 0.084 / Rsym value: 0.077 / Net I/av σ(I): 7.4 / Net I/σ(I): 14.5 / Num. measured all: 328804
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.48-1.5570.9550.866340.3851.0310.955100
1.55-1.657.20.6341.262530.2520.6830.634100
1.65-1.767.20.4431.759210.1770.4780.443100
1.76-1.97.20.2612.954760.1040.2820.261100
1.9-2.097.30.1465.150850.0580.1580.146100
2.09-2.337.30.0898.346200.0350.0960.089100
2.33-2.697.30.0661141140.0260.0710.066100
2.69-3.37.10.04614.735120.0190.050.046100
3.3-4.6670.03517.427480.0140.0380.035100
4.66-51.8056.50.03514.316210.0150.0380.03599.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2 Å39.54 Å
Translation2 Å39.54 Å

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
PHASER2.5.7phasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Ensemble of 2OSS, 2OUO, 2GRC, 2OO1, 3DAI, 3D7C, 3DWY

2oss

2ouo

2grc

2oo1

3dai

3d7c

3dwy


Resolution: 1.48→51.8 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.956 / SU B: 2.795 / SU ML: 0.052 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.071 / ESU R Free: 0.074
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2095 2061 4.5 %RANDOM
Rwork0.1771 ---
obs0.1786 43853 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 65.9 Å2 / Biso mean: 21.015 Å2 / Biso min: 9.82 Å2
Baniso -1Baniso -2Baniso -3
1-0.22 Å20 Å20 Å2
2--0.01 Å2-0 Å2
3----0.23 Å2
Refinement stepCycle: final / Resolution: 1.48→51.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2162 0 12 245 2419
Biso mean--25.8 30.97 -
Num. residues----262
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.022270
X-RAY DIFFRACTIONr_bond_other_d0.0020.022151
X-RAY DIFFRACTIONr_angle_refined_deg1.6541.9763095
X-RAY DIFFRACTIONr_angle_other_deg1.02634970
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7715267
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.90925.755106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.17715383
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.081155
X-RAY DIFFRACTIONr_chiral_restr0.1090.2332
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212540
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02509
LS refinement shellResolution: 1.475→1.513 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.314 171 -
Rwork0.29 3206 -
all-3377 -
obs--99.97 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.394-0.244-0.4160.37970.32140.5796-0.06040.00850.00630.00680.03750.00270.03850.01560.02290.0335-0.00350.00530.013-0.00270.06533.34262.142912.6876
20.1911-0.1186-0.42850.25780.15031.0535-0.03240.0155-0.0180.03360.0030.05420.0426-0.03990.02940.0334-0.00490.00690.00260.00320.078810.29972.428141.4257
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 168
2X-RAY DIFFRACTION2B43 - 167

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