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- PDB-6uwx: Cocrystal of BRD4(D1) with a ethyl carbamate thiazepane inhibitor -

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Basic information

Entry
Database: PDB / ID: 6uwx
TitleCocrystal of BRD4(D1) with a ethyl carbamate thiazepane inhibitor
ComponentsBromodomain-containing protein 4BRD4
KeywordsGENE REGULATION/INHIBITOR / BRD4(D1) / inhibitor / GENE REGULATION-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-QKD / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.307 Å
AuthorsJohnson, J.A. / Pomerantz, W.C.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Library of Medicine (NIH/NLM)5T32GM008347-23 United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains.
Authors: Johnson, J.A. / Nicolaou, C.A. / Kirberger, S.E. / Pandey, A.K. / Hu, H. / Pomerantz, W.C.K.
History
DepositionNov 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_residues
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)15,4333
Polymers15,0991
Non-polymers3332
Water3,531196
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.378, 44.337, 77.945
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 15099.380 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) / References: UniProt: O60885
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-QKD / ethyl (7S)-7-(thiophen-2-yl)-1,4-thiazepane-4-carboxylate


Mass: 271.399 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H17NO2S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 196 / 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: 2.26 Å3/Da / Density % sol: 45.6 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1 M bis-tris propane, 20 % PEG 3350 / PH range: 8-9 / Temp details: ambient temperature

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 1, 2019
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.307→28.58 Å / Num. obs: 31832 / % possible obs: 92.82 % / Redundancy: 4.8 % / Biso Wilson estimate: 12.16 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.0329 / Rpim(I) all: 0.01637 / Rrim(I) all: 0.03691 / Net I/σ(I): 29.42
Reflection shellResolution: 1.307→1.354 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.1178 / Mean I/σ(I) obs: 9.85 / Num. unique obs: 2684 / CC1/2: 0.984 / Rpim(I) all: 0.06246 / Rrim(I) all: 0.1338 / % possible all: 84.86

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
XDSdata reduction
XDSdata scaling
PHENIX1.15.2_3472phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 1.307→28.58 Å / SU ML: 0.1096 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 18.4149
RfactorNum. reflection% reflection
Rfree0.1922 --
Rwork0.1742 --
obs-29793 92.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 16.23 Å2
Refinement stepCycle: LAST / Resolution: 1.307→28.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1059 0 21 196 1276
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00481122
X-RAY DIFFRACTIONf_angle_d0.85461525
X-RAY DIFFRACTIONf_chiral_restr0.0751163
X-RAY DIFFRACTIONf_plane_restr0.0049195
X-RAY DIFFRACTIONf_dihedral_angle_d3.254712
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.31-1.340.22841260.20811762X-RAY DIFFRACTION82.95
1.34-1.380.22971350.1981861X-RAY DIFFRACTION89.55
1.38-1.420.23531370.18331908X-RAY DIFFRACTION90.25
1.42-1.460.20371290.18211800X-RAY DIFFRACTION86.58
1.46-1.510.18241410.17461961X-RAY DIFFRACTION91.91
1.51-1.580.19631440.17491989X-RAY DIFFRACTION93.88
1.58-1.650.20721440.17422003X-RAY DIFFRACTION94.71
1.65-1.730.21571460.18132038X-RAY DIFFRACTION96.55
1.73-1.840.20491490.1812054X-RAY DIFFRACTION96.24
1.84-1.980.18431450.1752027X-RAY DIFFRACTION94.93
1.98-2.180.20571500.16542075X-RAY DIFFRACTION96.61
2.18-2.50.20881520.17492106X-RAY DIFFRACTION97.33
2.5-3.150.18821510.17982105X-RAY DIFFRACTION96.58
3.15-28.580.16021510.16412105X-RAY DIFFRACTION91.3

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