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- PDB-4mr6: Crystal Structure of the second bromodomain of human BRD2 in comp... -

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Basic information

Entry
Database: PDB / ID: 4mr6
TitleCrystal Structure of the second bromodomain of human BRD2 in complex with a quinazolinone ligand (RVX-208)
ComponentsBromodomain-containing protein 2
KeywordsTRANSCRIPTION/TRANSCRIPTION inhibitor / BRD2 / RING3 / Small molecule inhibitor / RVX-208 / inhibitor complex / Structural Genomics Consortium / SGC / TRANSCRIPTION-TRANSCRIPTION inhibitor complex
Function / homology
Function and homology information


acetylation-dependent protein binding / chromatin looping / RUNX3 regulates p14-ARF / positive regulation of T-helper 17 cell lineage commitment / protein localization to chromatin / neural tube closure / lysine-acetylated histone binding / nucleosome assembly / spermatogenesis / nuclear speck ...acetylation-dependent protein binding / chromatin looping / RUNX3 regulates p14-ARF / positive regulation of T-helper 17 cell lineage commitment / protein localization to chromatin / neural tube closure / lysine-acetylated histone binding / nucleosome assembly / spermatogenesis / nuclear speck / protein serine/threonine kinase activity / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
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 ...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 / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-1K0 / Bromodomain-containing protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.67 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Felletar, I. / Martin, S. / Fedorov, O. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Weigelt, J. / Bountra, C. ...Filippakopoulos, P. / Picaud, S. / Felletar, I. / Martin, S. / Fedorov, O. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Weigelt, J. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2013
Title: RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain.
Authors: Picaud, S. / Wells, C. / Felletar, I. / Brotherton, D. / Martin, S. / Savitsky, P. / Diez-Dacal, B. / Philpott, M. / Bountra, C. / Lingard, H. / Fedorov, O. / Muller, S. / Brennan, P.E. / ...Authors: Picaud, S. / Wells, C. / Felletar, I. / Brotherton, D. / Martin, S. / Savitsky, P. / Diez-Dacal, B. / Philpott, M. / Bountra, C. / Lingard, H. / Fedorov, O. / Muller, S. / Brennan, P.E. / Knapp, S. / Filippakopoulos, P.
History
DepositionSep 17, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2014Group: Database references
Revision 1.2Sep 20, 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bromodomain-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0106
Polymers13,3751
Non-polymers6355
Water3,225179
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)32.118, 52.692, 72.119
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

#1: Protein Bromodomain-containing protein 2 / O27.1.1 / Really interesting new gene 3 protein


Mass: 13375.410 Da / Num. of mol.: 1 / Fragment: unp residues 344-455
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD2, KIAA9001, RING3 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: P25440
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-1K0 / 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxyquinazolin-4(3H)-one


Mass: 370.399 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22N2O5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 179 / Source method: isolated from a natural source / Formula: H2O

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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: 2.28 Å3/Da / Density % sol: 46.08 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 25% PEG3350, 0.2M KSCN, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.52 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jun 21, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.52 Å / Relative weight: 1
ReflectionRedundancy: 4.8 % / Av σ(I) over netI: 6.4 / Number: 66405 / Rsym value: 0.119 / D res high: 1.666 Å / D res low: 19.603 Å / Num. obs: 13910 / % possible obs: 93.9
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
5.2719.697.610.0380.0384.2
3.725.279910.0380.0384.6
3.043.7298.410.0470.0474.8
2.633.0497.810.0820.0824.8
2.362.6396.910.1180.1184.8
2.152.3696.110.1470.1474.9
1.992.1595.410.2060.2064.9
1.861.9994.110.3470.3474.9
1.761.8693.310.5310.5314.9
1.671.768210.7030.7034.6
ReflectionResolution: 1.67→19.6 Å / Num. all: 14814 / Num. obs: 13910 / % possible obs: 93.9 % / Redundancy: 4.8 % / Biso Wilson estimate: 12.8 Å2 / Rmerge(I) obs: 0.119 / Rsym value: 0.119 / Net I/σ(I): 11.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym value% possible all
1.67-1.764.60.703217210.70393.9
1.76-1.864.90.5313.118600.53196
1.86-1.994.90.3474.817920.34796.5
1.99-2.154.90.206816790.20697
2.15-2.364.90.1471115680.14797.5
2.36-2.634.80.11813.114500.11897.9
2.63-3.044.80.08217.612930.08298.3
3.04-3.724.80.04726.711190.04798.5
3.72-5.274.60.03831.59070.03898.5
5.27-19.64.20.03829.15210.03897.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å19.6 Å
Translation3.5 Å19.6 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
PHASER2.3.0phasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
StructureStudiodata collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3ONI

3oni


Resolution: 1.67→19.6 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.939 / WRfactor Rfree: 0.1715 / WRfactor Rwork: 0.1325 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.899 / SU B: 3.328 / SU ML: 0.06 / SU R Cruickshank DPI: 0.0992 / SU Rfree: 0.0996 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.099 / ESU R Free: 0.1 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.1932 700 5 %RANDOM
Rwork0.1549 ---
obs0.1568 13867 93.66 %-
all-14815 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 122.06 Å2 / Biso mean: 14.7968 Å2 / Biso min: 6.05 Å2
Baniso -1Baniso -2Baniso -3
1-0.58 Å20 Å20 Å2
2---0.38 Å20 Å2
3----0.2 Å2
Refinement stepCycle: LAST / Resolution: 1.67→19.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms907 0 43 179 1129
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.021008
X-RAY DIFFRACTIONr_bond_other_d0.0020.02705
X-RAY DIFFRACTIONr_angle_refined_deg1.5881.9891358
X-RAY DIFFRACTIONr_angle_other_deg1.01631705
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.655117
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.81123.450
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.30415174
X-RAY DIFFRACTIONr_dihedral_angle_4_deg26.1157
X-RAY DIFFRACTIONr_chiral_restr0.1020.2132
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0211217
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02214
LS refinement shellResolution: 1.67→1.713 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.283 31 -
Rwork0.284 723 -
all-754 -
obs--74.65 %
Refinement TLS params.Method: refined / Origin x: -1.1262 Å / Origin y: 36.6357 Å / Origin z: 33.5289 Å
111213212223313233
T0.0415 Å20 Å20.0008 Å2-0.0505 Å2-0.002 Å2--0.0588 Å2
L0.0526 °2-0.1106 °2-0.0942 °2-0.2738 °20.0664 °2--0.636 °2
S-0.0063 Å °0.0049 Å °-0.0029 Å °0.006 Å °-0.0099 Å °0.0074 Å °-0.0031 Å °0.0125 Å °0.0163 Å °

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