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- PDB-4ogi: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 4ogi
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor BI-2536
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION/INHIBITOR / bromodomain / bromodomain containing protein 4 / PLK1 kinase inhibitor / structural genomics / Structural Genomics Consortium / SGC / TRANSCRIPTION-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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader 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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader 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 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like ...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 / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-R78 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.73 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Jose, B. / Martin, S. / Fedorov, O. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Nat.Chem.Biol. / Year: 2014
Title: Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.
Authors: Ciceri, P. / Muller, S. / O'Mahony, A. / Fedorov, O. / Filippakopoulos, P. / Hunt, J.P. / Lasater, E.A. / Pallares, G. / Picaud, S. / Wells, C. / Martin, S. / Wodicka, L.M. / Shah, N.P. / ...Authors: Ciceri, P. / Muller, S. / O'Mahony, A. / Fedorov, O. / Filippakopoulos, P. / Hunt, J.P. / Lasater, E.A. / Pallares, G. / Picaud, S. / Wells, C. / Martin, S. / Wodicka, L.M. / Shah, N.P. / Treiber, D.K. / Knapp, S.
History
DepositionJan 16, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 26, 2014Provider: repository / Type: Initial release
Revision 1.1Apr 2, 2014Group: Database references
Revision 1.2Jan 31, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Sep 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)31,3666
Polymers30,1992
Non-polymers1,1674
Water4,612256
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6833
Polymers15,0991
Non-polymers5842
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6833
Polymers15,0991
Non-polymers5842
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.243, 59.640, 115.345
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.: 2 / Fragment: bromodomain 1 (UNP residues 44-168)
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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-R78 / 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide


Mass: 521.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H39N7O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 256 / 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: 2.41 Å3/Da / Density % sol: 48.87 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.2 M potassium citrate, 0.1 M Bis-Tris propane, pH 8.5, 20.0% PEG3350, 10% ethylene glycol, 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 4, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.52 Å / Relative weight: 1
ReflectionRedundancy: 4.6 % / Av σ(I) over netI: 6.9 / Number: 144652 / Rsym value: 0.094 / D res high: 1.73 Å / D res low: 19.62 Å / Num. obs: 31157 / % possible obs: 99.7
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
5.4719.6297.410.0310.0314.4
3.875.4799.910.0330.0334.6
3.163.8799.910.0430.0434.7
2.743.1610010.0690.0694.7
2.452.7499.910.1050.1054.7
2.232.4599.910.140.144.7
2.072.2399.910.1840.1844.7
1.932.0799.910.2880.2884.7
1.821.9399.510.4590.4594.6
1.731.8299.510.7720.7724.5
ReflectionResolution: 1.73→19.62 Å / Num. all: 31251 / Num. obs: 31157 / % possible obs: 99.7 % / Redundancy: 4.6 % / Biso Wilson estimate: 18.5 Å2 / Rmerge(I) obs: 0.094 / Rsym value: 0.094 / Net I/σ(I): 11.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.73-1.824.50.7720.62016844680.77299.5
1.82-1.934.60.4591.71938442140.45999.5
1.93-2.074.70.2882.71867540130.28899.9
2.07-2.234.70.1844.21743537320.18499.9
2.23-2.454.70.145.51618734340.1499.9
2.45-2.744.70.1057.31486331440.10599.9
2.74-3.164.70.06910.91327828040.069100
3.16-3.874.70.04316.41121023910.04399.9
3.87-5.474.60.03319.6874818830.03399.9
5.47-19.624.40.03118.8470410740.03197.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 52.19 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å19.62 Å
Translation2.5 Å19.62 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.21data scaling
PHASER2.1.4phasing
REFMAC5.7.0032refinement
PDB_EXTRACT3.14data extraction
CrystalCleardata collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2OSS

2oss


Resolution: 1.73→19.62 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.944 / WRfactor Rfree: 0.192 / WRfactor Rwork: 0.1581 / FOM work R set: 0.8778 / SU B: 4.308 / SU ML: 0.077 / SU R Cruickshank DPI: 0.1098 / SU Rfree: 0.1091 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.11 / ESU R Free: 0.109 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2139 1566 5 %RANDOM
Rwork0.1756 ---
all0.1775 31233 --
obs0.1775 31083 99.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 84.06 Å2 / Biso mean: 23.247 Å2 / Biso min: 8.45 Å2
Baniso -1Baniso -2Baniso -3
1-0.46 Å20 Å2-0 Å2
2---0.69 Å20 Å2
3---0.23 Å2
Refinement stepCycle: LAST / Resolution: 1.73→19.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2112 0 84 256 2452
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.022283
X-RAY DIFFRACTIONr_bond_other_d0.0010.022173
X-RAY DIFFRACTIONr_angle_refined_deg1.6452.0083114
X-RAY DIFFRACTIONr_angle_other_deg0.83535024
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2035258
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.3925.818110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.27115391
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.503157
X-RAY DIFFRACTIONr_chiral_restr0.0910.2325
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212730
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02509
X-RAY DIFFRACTIONr_mcbond_it2.7061.9821020
X-RAY DIFFRACTIONr_mcbond_other2.6831.9761019
X-RAY DIFFRACTIONr_mcangle_it3.1253.6791273
LS refinement shellResolution: 1.73→1.775 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 107 -
Rwork0.279 2098 -
all-2205 -
obs--97.83 %
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)
12.3842-0.8336-0.7423.52271.28483.57060.02840.0173-0.0282-0.08460.0286-0.14920.07510.1543-0.0570.0276-0.01010.00390.0181-0.0030.009131.74922.452212.0875
21.99520.6175-0.83642.5693-0.68822.1477-0.1209-0.0608-0.14340.02280.05570.04370.1031-0.08890.06520.03280.01880.00570.02350.00120.01559.16741.783544.8974
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 168
2X-RAY DIFFRACTION2B42 - 168

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