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- PDB-7t3f: Development of BRD4 inhibitors as arsenicals antidotes -

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Basic information

Entry
Database: PDB / ID: 7t3f
TitleDevelopment of BRD4 inhibitors as arsenicals antidotes
ComponentsBromodomain-containing protein 4
KeywordsGENE REGULATION / Bromodomain-containing protein / DNA damage / antidotes / BRD4 inhibitors
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 II / Brdt, bromodomain, repeat I / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-EM0 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.28 Å
AuthorsWu, M. / Yatchang, M. / Mathew, B. / Zhai, L. / Ruiz, P. / Bostwick, R. / Augelli-Szafran, C.E. / Suto, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)5-U54ES030246-04 United States
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2022
Title: Development of BRD4 inhibitors as anti-inflammatory agents and antidotes for arsenicals.
Authors: Yatchang, M.F. / Mathew, B. / Srivastava, R.K. / Khan, J. / Muzaffar, S. / Zhang, S. / Wu, M. / Zhai, L. / Ruiz, P. / Agarwal, A. / Bostwick, J.R. / Suto, M.J. / Athar, M. / Augelli-Szafran, C.E.
History
DepositionDec 7, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)15,7045
Polymers15,0781
Non-polymers6264
Water3,333185
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)34.913, 46.973, 77.593
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 / Protein HUNK1


Mass: 15078.386 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL-21 DE3 / References: UniProt: O60885
#2: Chemical ChemComp-EM0 / 4-fluoro-3-methyl-N-(3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)benzene-1-sulfonamide


Mass: 349.380 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16FN3O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 185 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.11 Å3/Da / Density % sol: 41.7 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.4
Details: 20% PEG 3350, 0.2 M ammonium acetate, 0.1 M HEPES, pH7.4

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 27, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.28→40.18 Å / Num. obs: 33664 / % possible obs: 98.8 % / Redundancy: 7.2 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 27.4
Reflection shellResolution: 1.28→1.3 Å / Rmerge(I) obs: 0.144 / Num. unique obs: 1732

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
SCALAdata scaling
PHASERphasing
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WMD

5wmd


Resolution: 1.28→26.37 Å / Cor.coef. Fo:Fc: 0.98 / Cor.coef. Fo:Fc free: 0.975 / SU B: 0.971 / SU ML: 0.019 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.041 / ESU R Free: 0.039 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1446 1698 5.1 %RANDOM
Rwork0.1195 ---
obs0.1208 31473 98.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 54.16 Å2 / Biso mean: 15.671 Å2 / Biso min: 8.84 Å2
Baniso -1Baniso -2Baniso -3
1-0.71 Å20 Å20 Å2
2---0.13 Å20 Å2
3----0.58 Å2
Refinement stepCycle: final / Resolution: 1.28→26.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1060 0 42 185 1287
Biso mean--22.34 29.24 -
Num. residues----127
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0131156
X-RAY DIFFRACTIONr_bond_other_d0.0020.0171097
X-RAY DIFFRACTIONr_angle_refined_deg1.5811.6931572
X-RAY DIFFRACTIONr_angle_other_deg1.5461.62539
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9085131
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.7652558
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.05415200
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.487153
X-RAY DIFFRACTIONr_chiral_restr0.4860.2144
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.021270
X-RAY DIFFRACTIONr_gen_planes_other0.0090.02258
X-RAY DIFFRACTIONr_rigid_bond_restr1.65232253
LS refinement shellResolution: 1.28→1.313 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.156 109 -
Rwork0.114 2251 -
all-2360 -
obs--96.41 %

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