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- PDB-6yin: Crystal structure of the first bromodomain of BRD4 in complex wit... -

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Basic information

Entry
Database: PDB / ID: 6yin
TitleCrystal structure of the first bromodomain of BRD4 in complex with a benzo-diazepine ligand
ComponentsBromodomain-containing protein 4BRD4
KeywordsTRANSCRIPTION / Bromodomain / BRD4 / small molecule / benzo-diazepine / SGC / Structural Genomics Consortium
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II ...RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / lysine-acetylated histone binding / p53 binding / chromosome / regulation of inflammatory response / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus
Similarity search - Function
Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-OS8 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.53 Å
AuthorsPicaud, S. / Brand, M. / Tobias, K. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Conway, S. / Filippakopoulos, P.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/N010051/1 United Kingdom
CitationJournal: To Be Published
Title: Crystal structure of the first bromodomain of BRD4 in complex with a benzo-diazepine ligand
Authors: Picaud, S. / Brand, M. / Tobias, K. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Conway, S. / Filippakopoulos, P.
History
DepositionApr 1, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 24, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5222
Polymers15,0991
Non-polymers4231
Water1,31573
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.603, 48.347, 58.962
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 / BRD4 / 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) / References: UniProt: O60885
#2: Chemical ChemComp-OS8 / (4~{R})-~{N}-[3-(7-methoxy-3,4-dihydro-2~{H}-quinolin-1-yl)propyl]-4-methyl-2-oxidanylidene-1,3,4,5-tetrahydro-1,5-benzodiazepine-6-carboxamide


Mass: 422.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H30N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 73 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.96 Å3/Da / Density % sol: 37.36 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 30% PEG1000 0.1M MIB pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 1.52→58.9 Å / Num. obs: 18722 / % possible obs: 99.9 % / Redundancy: 6.3 % / Rpim(I) all: 0.022 / Rrim(I) all: 0.054 / Rsym value: 0.049 / Net I/av σ(I): 5.9 / Net I/σ(I): 15.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.52-1.616.70.746126860.3110.810.746100
1.61-1.716.60.441.725210.1860.4780.44100
1.71-1.826.20.2822.724050.1230.3090.282100
1.82-1.976.60.1754.222490.0740.190.175100
1.97-2.166.40.0977.220530.0420.1060.09799.8
2.16-2.4160.06710.318920.030.0730.06799.9
2.41-2.786.30.05212.216700.0220.0560.05299.8
2.78-3.415.80.0414.114270.0180.0440.0499.7
3.41-4.8260.03813.911410.0170.0410.03899.8
4.82-58.95.40.03613.26780.0170.040.03699.8

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å37.39 Å
Translation2.5 Å37.39 Å

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
PHASER2.8.2phasing
REFMAC5.8.0232refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 1.53→37.39 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.95 / SU B: 4.202 / SU ML: 0.078 / SU R Cruickshank DPI: 0.0937 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.094 / ESU R Free: 0.097
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.245 910 4.9 %RANDOM
Rwork0.2042 ---
obs0.2062 17763 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 91.95 Å2 / Biso mean: 27.952 Å2 / Biso min: 17.81 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å20 Å20 Å2
2--1.32 Å2-0 Å2
3----1.09 Å2
Refinement stepCycle: final / Resolution: 1.53→37.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1033 0 31 73 1137
Biso mean--32.86 35.35 -
Num. residues----126
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0131114
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171004
X-RAY DIFFRACTIONr_angle_refined_deg2.1611.6931523
X-RAY DIFFRACTIONr_angle_other_deg1.5431.5732353
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5165129
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.3425.28353
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.16515185
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.878152
X-RAY DIFFRACTIONr_chiral_restr0.1080.2141
X-RAY DIFFRACTIONr_gen_planes_refined0.0160.021202
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02208
LS refinement shellResolution: 1.53→1.565 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.369 70 -
Rwork0.277 1274 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 34.4015 Å / Origin y: 32.9315 Å / Origin z: 12.195 Å
111213212223313233
T0.0188 Å2-0.0165 Å2-0.0026 Å2-0.0387 Å20.0032 Å2--0.1524 Å2
L1.2944 °2-0.1103 °2-0.2675 °2-0.8651 °2-0.3027 °2--1.1572 °2
S-0.0586 Å °-0.0592 Å °-0.0522 Å °0.0434 Å °0.0092 Å °-0.0281 Å °0.0296 Å °0.0613 Å °0.0494 Å °

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