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- PDB-5fbx: Crystal structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 5fbx
TitleCrystal structure of the first bromodomain of human BRD4 in complex with PNZ5 isoxazole inhibitor
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / BRG1-associated factor 180 / BAF180 / chromatin remodeling
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-5W4 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsTallant, C. / Clark, P.G.K. / Siejka, P. / Fedorov, O. / Nowak, R. / Srikannathasan, V. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. ...Tallant, C. / Clark, P.G.K. / Siejka, P. / Fedorov, O. / Nowak, R. / Srikannathasan, V. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Muller, S. / Brennan, P.E. / Dixon, D. / Knapp, S.
CitationJournal: To Be Published
Title: Crystal structure of the first bromodomain of human BRD4 in complex with PNZ5 isoxazole inhibitor
Authors: Tallant, C. / Clark, P.G.K. / Siejka, P. / Fedorov, O. / Nowak, R. / Srikannathasan, V. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Muller, S. / Brennan, P.E. / Dixon, D. / Knapp, S.
History
DepositionDec 14, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Dec 30, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 10, 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

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4182
Polymers15,0991
Non-polymers3181
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.296, 44.520, 79.767
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 15099.380 Da / Num. of mol.: 1 / Fragment: 1st bromodomain, 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) / References: UniProt: O60885
#2: Chemical ChemComp-5W4 / (3~{S})-5-(3,5-dimethyl-1,2-oxazol-4-yl)-2-methyl-3-phenyl-3~{H}-isoindol-1-one


Mass: 318.369 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18N2O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 87 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.31 Å3/Da / Density % sol: 46.86 % / Description: Rod
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 7.8
Details: 20 % PEG 3350, 0.2 M zinc acetate, 0.1 M imidazole pH 7.8
PH range: 7.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 6, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.85→29.71 Å / Num. all: 12496 / Num. obs: 12496 / % possible obs: 99.6 % / Redundancy: 9.6 % / Biso Wilson estimate: 15.371 Å2 / Rmerge(I) obs: 0.095 / Rsym value: 0.046 / Net I/σ(I): 18.9
Reflection shellResolution: 1.85→1.89 Å / Redundancy: 9.7 % / Rmerge(I) obs: 0.998 / Mean I/σ(I) obs: 2.3 / % possible all: 98.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0107refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 1.85→29.71 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.908 / SU B: 7.916 / SU ML: 0.131 / Cross valid method: THROUGHOUT / ESU R: 0.162 / ESU R Free: 0.158 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26663 610 4.9 %RANDOM
Rwork0.21239 ---
obs0.21516 11826 99.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.265 Å2
Baniso -1Baniso -2Baniso -3
1-1.68 Å20 Å20 Å2
2---0.23 Å20 Å2
3----1.45 Å2
Refinement stepCycle: 1 / Resolution: 1.85→29.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1061 0 24 87 1172
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0191118
X-RAY DIFFRACTIONr_bond_other_d0.0020.021059
X-RAY DIFFRACTIONr_angle_refined_deg2.0061.9531524
X-RAY DIFFRACTIONr_angle_other_deg1.15732447
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5495126
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.65125.92654
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.68415197
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.336153
X-RAY DIFFRACTIONr_chiral_restr0.3820.2159
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211350
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02251
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4031.871507
X-RAY DIFFRACTIONr_mcbond_other1.3971.865506
X-RAY DIFFRACTIONr_mcangle_it2.1892.791633
X-RAY DIFFRACTIONr_mcangle_other2.1872.792634
X-RAY DIFFRACTIONr_scbond_it1.8152.068611
X-RAY DIFFRACTIONr_scbond_other1.8132.068612
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.8983.007892
X-RAY DIFFRACTIONr_long_range_B_refined4.35915.241347
X-RAY DIFFRACTIONr_long_range_B_other4.35815.2431348
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.847→1.895 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 59 -
Rwork0.263 820 -
obs--97.67 %
Refinement TLS params.Method: refined / Origin x: 7.8452 Å / Origin y: 19.1249 Å / Origin z: 9.7018 Å
111213212223313233
T0.0251 Å2-0.0004 Å20.0188 Å2-0.0041 Å20.0035 Å2--0.0544 Å2
L0.5147 °20.2889 °2-0.5176 °2-0.7014 °2-0.6775 °2--1.4428 °2
S-0.0881 Å °-0.0052 Å °-0.0002 Å °-0.0404 Å °-0.0302 Å °-0.086 Å °0.1163 Å °-0.0155 Å °0.1183 Å °

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