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- PDB-4mr5: Crystal Structure of the second bromodomain of human BRD2 in comp... -

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Basic information

Entry
Database: PDB / ID: 4mr5
TitleCrystal Structure of the second bromodomain of human BRD2 in complex with a quinazolinone ligand (RVX-OH)
ComponentsBromodomain-containing protein 2
KeywordsTRANSCRIPTION/TRANSCRIPTION inhibitor / BRD2 / RING3 / Small molecule inhibitor / RVX-OH / 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 II / Brdt, bromodomain, repeat I / 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 II / Brdt, bromodomain, repeat I / 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: 1.63 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 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)14,0727
Polymers13,3751
Non-polymers6976
Water2,540141
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.220, 72.008, 32.039
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-741-

HOH

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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.: 4 / 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.: 141 / 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: 2.25 Å3/Da / Density % sol: 45.38 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.20M Na(formate), 0.1M BTProp, 20.0% PEG 3350 10.0% EtGly, pH 8.5, 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: Feb 14, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.52 Å / Relative weight: 1
ReflectionRedundancy: 4.3 % / Av σ(I) over netI: 14.6 / Number: 67544 / Rsym value: 0.038 / D res high: 1.63 Å / D res low: 19.21 Å / Num. obs: 15616 / % possible obs: 99.5
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
5.1519.2197.310.0240.0244.2
3.645.1510010.0250.0254.5
2.983.6499.910.0280.0284.6
2.582.9810010.0340.0344.6
2.312.5899.810.0390.0394.6
2.12.3199.910.0450.0454.6
1.952.199.910.0590.0594.6
1.821.9510010.0910.0914.5
1.721.8299.810.1330.1334.4
1.631.7297.510.170.173.1
ReflectionResolution: 1.63→19.49 Å / Num. all: 15694 / Num. obs: 15616 / % possible obs: 99.5 % / Redundancy: 4.3 % / Biso Wilson estimate: 14 Å2 / Rmerge(I) obs: 0.038 / Rsym value: 0.038 / Net I/σ(I): 21.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym value% possible all
1.63-1.723.10.17621840.1799.5
1.72-1.824.40.0918.921130.09199.8
1.82-1.954.50.0911320030.09199.8
1.95-2.14.60.05919.118870.05999.8
2.1-2.314.60.04524.517330.04599.7
2.31-2.584.60.03928.315600.03999.7
2.58-3.984.60.03432.814140.03499.6
2.98-3.644.60.02839.912160.02899.4
3.64-5.154.50.02544.39520.02599
5.15-19.494.20.02441.55540.02497.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 46.6 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å19.21 Å
Translation2.5 Å19.21 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.21data scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
StructureStudiodata collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.63→19.22 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.952 / WRfactor Rfree: 0.1581 / WRfactor Rwork: 0.1298 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.907 / SU B: 2.532 / SU ML: 0.046 / SU R Cruickshank DPI: 0.0731 / SU Rfree: 0.0768 / Isotropic thermal model: pdb entry 3ONI / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.073 / ESU R Free: 0.077 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.1698 780 5 %RANDOM
Rwork0.1357 ---
obs0.1374 15580 99.32 %-
all-15687 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 87.12 Å2 / Biso mean: 15.8516 Å2 / Biso min: 5.63 Å2
Baniso -1Baniso -2Baniso -3
1-0.08 Å20 Å20 Å2
2---0.48 Å2-0 Å2
3---0.4 Å2
Refinement stepCycle: LAST / Resolution: 1.63→19.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms910 0 44 141 1095
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.02976
X-RAY DIFFRACTIONr_bond_other_d0.0020.02927
X-RAY DIFFRACTIONr_angle_refined_deg1.6261.9921309
X-RAY DIFFRACTIONr_angle_other_deg0.86332128
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4235109
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.24223.54248
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.48715167
X-RAY DIFFRACTIONr_dihedral_angle_4_deg27.847156
X-RAY DIFFRACTIONr_chiral_restr0.1060.2129
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211172
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02230
X-RAY DIFFRACTIONr_mcbond_it2.7451.397439
X-RAY DIFFRACTIONr_mcbond_other2.7471.407440
X-RAY DIFFRACTIONr_mcangle_it2.9682.566547
LS refinement shellResolution: 1.63→1.672 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.195 56 -
Rwork0.15 1012 -
all-1068 -
obs--95.36 %
Refinement TLS params.Method: refined / Origin x: 36.3254 Å / Origin y: 2.6082 Å / Origin z: 16.9172 Å
111213212223313233
T0.0387 Å20.0018 Å2-0.0025 Å2-0.0384 Å2-0.0012 Å2--0.0308 Å2
L0.247 °20.0334 °20.0519 °2-0.6253 °2-0.1005 °2--0.0304 °2
S-0.021 Å °-0.008 Å °-0.0089 Å °-0.0178 Å °0.0271 Å °-0.0048 Å °-0.0009 Å °-0.0033 Å °-0.0061 Å °

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