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- PDB-3u5k: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 3u5k
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with Midazolam
ComponentsBromodomain-containing protein 4BRD4
KeywordsSIGNALING PROTEIN/INHIBITOR / Bromodomain-containing protein 4 isoform long / BRD4 / Bromodomain containing protein 4 / CAP / HUNK1 / MCAP / Mitotic chromosome associated protein / Structural Genomics Consortium / SGC / SIGNALING PROTEIN-INHIBITOR complex
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-08J / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Felletar, I. / Fedorov, O. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Weigelt, J. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Bioorg.Med.Chem. / Year: 2012
Title: Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family.
Authors: Filippakopoulos, P. / Picaud, S. / Fedorov, O. / Keller, M. / Wrobel, M. / Morgenstern, O. / Bracher, F. / Knapp, S.
History
DepositionOct 11, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2011Provider: repository / Type: Initial release
Revision 1.1Mar 7, 2012Group: Database references
Revision 1.2Mar 21, 2012Group: Database references
Revision 1.3Sep 13, 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

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: Bromodomain-containing protein 4
C: Bromodomain-containing protein 4
D: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,7018
Polymers60,3984
Non-polymers1,3034
Water4,161231
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4252
Polymers15,0991
Non-polymers3261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4252
Polymers15,0991
Non-polymers3261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4252
Polymers15,0991
Non-polymers3261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4252
Polymers15,0991
Non-polymers3261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.550, 89.550, 64.411
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31

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Components

#1: Protein
Bromodomain-containing protein 4 / BRD4 / Protein HUNK1


Mass: 15099.380 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: O60885
#2: Chemical
ChemComp-08J / 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine / Midazolam / Midazolam


Mass: 325.767 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H13ClFN3 / Comment: medication*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 231 / 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: 2.47 Å3/Da / Density % sol: 50.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1M MES pH 5.5, 0.1M MgCl, 15% PEG 6000, 10% EtGly, 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: Sep 25, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.52 Å / Relative weight: 1
ReflectionRedundancy: 4.1 % / Av σ(I) over netI: 5.3 / Number: 209166 / Rsym value: 0.102 / D res high: 1.8 Å / D res low: 26.145 Å / Num. obs: 51230 / % possible obs: 95.7
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
5.6926.1598.710.0710.0715
4.025.6910010.0760.0765
3.294.0210010.0780.0785
2.853.2999.810.0930.0934.9
2.552.8599.210.110.114.7
2.322.5599.110.1340.1344.3
2.152.3298.510.160.163.8
2.012.1596.510.2090.2093.4
1.92.019210.3280.3283.2
1.81.983.910.5220.5223.4
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.505
11K, H, -L20.495
ReflectionResolution: 1.8→26.68 Å / Num. all: 53532 / Num. obs: 51230 / % possible obs: 95.7 % / Redundancy: 4.1 % / Biso Wilson estimate: 21.7 Å2 / Rmerge(I) obs: 0.102 / Rsym value: 0.102 / Net I/σ(I): 7.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.8-1.93.40.5221.52195265510.52283.9
1.9-2.013.20.3282.32210368520.32892
2.01-2.153.40.2093.62290567000.20996.5
2.15-2.323.80.164.62437463340.1698.5
2.32-2.554.30.1345.42580659350.13499.1
2.55-2.854.70.116.32516453330.1199.2
2.85-3.294.90.0937.12312047410.09399.8
3.29-4.0250.0787.91994640240.078100
4.02-5.6950.0767.71538230680.076100
5.69-26.14550.0717.8841416920.07198.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 44.95 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å26.14 Å
Translation2.5 Å26.14 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 1.8→26.68 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.906 / WRfactor Rfree: 0.2641 / WRfactor Rwork: 0.2134 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.797 / SU B: 6.613 / SU ML: 0.103 / SU R Cruickshank DPI: 0.0306 / SU Rfree: 0.0305 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.03 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS; U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2599 1921 3.8 %RANDOM
Rwork0.2097 ---
all0.2116 53597 --
obs0.2116 51217 95.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 70.76 Å2 / Biso mean: 20.5613 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.38 Å20 Å20 Å2
2--0.38 Å20 Å2
3----0.76 Å2
Refinement stepCycle: LAST / Resolution: 1.8→26.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4035 0 92 231 4358
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0224278
X-RAY DIFFRACTIONr_bond_other_d0.0010.022876
X-RAY DIFFRACTIONr_angle_refined_deg1.641.9955848
X-RAY DIFFRACTIONr_angle_other_deg1.0113.0027023
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1355491
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.94125.344189
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.96115713
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9551512
X-RAY DIFFRACTIONr_chiral_restr0.0890.2624
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0214624
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02772
LS refinement shellResolution: 1.799→1.846 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.434 140 -
Rwork0.323 3088 -
all-3228 -
obs--80.76 %
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)
10.1470.2349-0.0830.559-0.0570.1032-0.00310.04150.0050.04480.0320.00760.0042-0.0004-0.02890.10090.00480.01250.1021-0.00490.144579.4678.860411.4359
20.453-0.06210.05810.37780.03290.028-0.01570.0260.00810.02990.05360.0198-0.0146-0.0055-0.03790.10170.01410.00890.11920.01650.125186.95239.2403-1.8961
30.376-0.2074-0.01710.4689-0.29230.26690.0011-0.05010.0131-0.07720.05260.02160.0538-0.0362-0.05380.0919-0.01690.01710.10610.00140.133265.147825.313232.9712
40.3897-0.4151-0.18650.48220.20340.09680.0649-0.03390.0118-0.0472-0.0235-0.022-0.03210.0082-0.04140.1208-0.01810.01590.09060.01990.152956.451446.808711.4293
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 167
2X-RAY DIFFRACTION2B43 - 166
3X-RAY DIFFRACTION3C43 - 165
4X-RAY DIFFRACTION4D42 - 167

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