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- PDB-6g0o: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 6g0o
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with an acetylated ATRX peptide (K1030ac/K1033ac)
Components
  • Bromodomain-containing protein 4
  • Transcriptional regulator ATRX
KeywordsTRANSCRIPTION / Bromodomain / complex
Function / homology
Function and homology information


post-embryonic forelimb morphogenesis / Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations / Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations / positive regulation of nuclear cell cycle DNA replication / negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric / chromosome, subtelomeric region / chromosome organization involved in meiotic cell cycle / Sertoli cell development / cellular response to hydroxyurea / meiotic spindle organization ...post-embryonic forelimb morphogenesis / Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations / Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations / positive regulation of nuclear cell cycle DNA replication / negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric / chromosome, subtelomeric region / chromosome organization involved in meiotic cell cycle / Sertoli cell development / cellular response to hydroxyurea / meiotic spindle organization / chromo shadow domain binding / DNA translocase activity / condensed chromosome, centromeric region / histone H3K9me2/3 reader activity / protein localization to chromosome, telomeric region / nuclear chromosome / seminiferous tubule development / positive regulation of telomere maintenance / replication fork processing / RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / host-mediated suppression of viral transcription / : / forebrain development / subtelomeric heterochromatin formation / positive regulation of T-helper 17 cell lineage commitment / pericentric heterochromatin / heterochromatin / positive regulation of G2/M transition of mitotic cell cycle / Inhibition of DNA recombination at telomere / RNA polymerase II CTD heptapeptide repeat kinase activity / : / histone reader activity / condensed nuclear chromosome / transcription coregulator activity / DNA damage response, signal transduction by p53 class mediator / positive regulation of transcription elongation by RNA polymerase II / helicase activity / PML body / chromatin DNA binding / multicellular organism growth / p53 binding / nucleosome assembly / chromosome / chromatin organization / regulation of inflammatory response / spermatogenesis / DNA helicase / histone binding / Potential therapeutics for SARS / transcription by RNA polymerase II / transcription coactivator activity / chromosome, telomeric region / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / nuclear body / chromatin remodeling / DNA repair / protein serine/threonine kinase activity / DNA damage response / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / chromatin / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / zinc ion binding / nucleoplasm / ATP binding / nucleus
Similarity search - Function
ATRX, ADD domain / : / Cysteine Rich ADD domain / ADD domain / ADD domain profile. / : / SNF2-like, N-terminal domain superfamily / SNF2, N-terminal / SNF2-related domain / Bromodomain protein 4, C-terminal ...ATRX, ADD domain / : / Cysteine Rich ADD domain / ADD domain / ADD domain profile. / : / SNF2-like, N-terminal domain superfamily / SNF2, N-terminal / SNF2-related domain / 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-like / Histone Acetyltransferase; Chain A / Zinc finger, FYVE/PHD-type / Helicase conserved C-terminal domain / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain (BrD) profile. / Bromodomain / Bromodomain-like superfamily / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Zinc finger, RING/FYVE/PHD-type / Up-down Bundle / P-loop containing nucleoside triphosphate hydrolase / Mainly Alpha
Similarity search - Domain/homology
Bromodomain-containing protein 4 / Transcriptional regulator ATRX
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.4 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Newman, J. / Sorrell, F. / 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
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
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 13, 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
B: Transcriptional regulator ATRX
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,7305
Polymers16,5442
Non-polymers1863
Water3,027168
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1780 Å2
ΔGint-1 kcal/mol
Surface area8240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.864, 52.797, 53.317
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.: 1
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 Transcriptional regulator ATRX / ATP-dependent helicase ATRX / X-linked helicase II / X-linked nuclear protein / XNP / Znf-HX


Mass: 1444.718 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: ATRX peptide acetylated at K1030 and K1033 C-terminal TYR added for UV detection
Source: (synth.) Homo sapiens (human) / References: UniProt: P46100, DNA helicase
#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.: 168 / 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: 2.11 Å3/Da / Density % sol: 41.75 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 20.0 % PEG 6K 10.0 % EtGly 0.1 M HEPES pH 7.0 0.2 M LiCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.4→53.317 Å / Num. obs: 27568 / % possible obs: 99.2 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.073 / Rpim(I) all: 0.031 / Rrim(I) all: 0.08 / Rsym value: 0.073 / Net I/av σ(I): 5.2 / Net I/σ(I): 17.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.4-1.4860.3881.838960.1720.4250.38898
1.48-1.576.10.2612.537350.1140.2850.26198.6
1.57-1.676.80.1753.835180.0720.1890.17599.1
1.67-1.816.60.1195.632970.0490.1290.11999.1
1.81-1.986.30.081830540.0350.0890.08199.5
1.98-2.216.80.0639.727930.0260.0680.06399.7
2.21-2.566.40.0591024860.0250.0650.05999.9
2.56-3.136.30.05310.621300.0230.0580.05399.9
3.13-4.436.30.0579.316750.0250.0630.057100
4.43-53.3175.60.0777.29840.0350.0850.07799.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2 Å37.52 Å
Translation2 Å37.52 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: 1.4→37.52 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.962 / SU B: 1.754 / SU ML: 0.031 / SU R Cruickshank DPI: 0.0589 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.059 / ESU R Free: 0.054
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1661 1186 4.3 %RANDOM
Rwork0.1336 ---
obs0.135 26339 98.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 61.27 Å2 / Biso mean: 16.198 Å2 / Biso min: 6.16 Å2
Baniso -1Baniso -2Baniso -3
1--0.1 Å20 Å20 Å2
2--0.87 Å2-0 Å2
3----0.78 Å2
Refinement stepCycle: final / Resolution: 1.4→37.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1141 0 12 168 1321
Biso mean--27.42 28.16 -
Num. residues----136
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.021218
X-RAY DIFFRACTIONr_bond_other_d0.0020.021179
X-RAY DIFFRACTIONr_angle_refined_deg1.7231.9851649
X-RAY DIFFRACTIONr_angle_other_deg0.94532720
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.235137
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.79425.17258
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.91715209
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.214154
X-RAY DIFFRACTIONr_chiral_restr0.1070.2174
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.0211343
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02277
X-RAY DIFFRACTIONr_rigid_bond_restr3.59632397
X-RAY DIFFRACTIONr_sphericity_free25.458549
X-RAY DIFFRACTIONr_sphericity_bonded9.06552485
LS refinement shellResolution: 1.4→1.436 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.293 82 -
Rwork0.279 1871 -
all-1953 -
obs--97.26 %

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