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- PDB-6uvm: Cocrystal of BRD4(D1) with a methyl carbamate thiazepane inhibitor -

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Basic information

Entry
Database: PDB / ID: 6uvm
TitleCocrystal of BRD4(D1) with a methyl carbamate thiazepane inhibitor
ComponentsBromodomain-containing protein 4
KeywordsGENE REGULATION/INHIBITOR / BRD4(D1) / inhibitor / GENE REGULATION-INHIBITOR complex
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / transcription coactivator activity / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / chromatin remodeling / protein serine/threonine kinase activity / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / 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 / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-QJA / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.51 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 3, 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)15,4013
Polymers15,0991
Non-polymers3012
Water1,60389
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.359, 44.240, 78.326
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 / 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-QJA / 1-[(7S)-7-(thiophen-2-yl)-6,7-dihydro-1,4-thiazepin-4(5H)-yl]ethan-1-one


Mass: 239.357 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H13NOS2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 89 / 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: 2.27 Å3/Da / Density % sol: 45.7 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: 0.1 M bis-tris propane, 20% ethylene glycol, and 20% PEG3350
PH range: 6.5-7.0 / 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: MAD / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.509→39.16 Å / Num. obs: 20911 / % possible obs: 98.81 % / Redundancy: 5.1 % / Biso Wilson estimate: 12.52 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.04872 / Rpim(I) all: 0.02333 / Rrim(I) all: 0.05425 / Net I/σ(I): 25.22
Reflection shellResolution: 1.509→1.563 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.3294 / Mean I/σ(I) obs: 5.95 / Num. unique obs: 2056 / CC1/2: 0.886 / Rpim(I) all: 0.1593 / Rrim(I) all: 0.3673 / % possible all: 98.75

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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: 3QZS

3qzs


Resolution: 1.51→39.16 Å / SU ML: 0.1485 / Cross valid method: NONE / σ(F): 1.37 / Phase error: 19.2518
RfactorNum. reflection% reflection
Rfree0.2182 2000 9.59 %
Rwork0.1875 --
obs0.1905 20856 98.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 14.57 Å2
Refinement stepCycle: LAST / Resolution: 1.51→39.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1057 0 19 89 1165
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00681116
X-RAY DIFFRACTIONf_angle_d1.00411519
X-RAY DIFFRACTIONf_chiral_restr0.0563163
X-RAY DIFFRACTIONf_plane_restr0.0054196
X-RAY DIFFRACTIONf_dihedral_angle_d2.6015958
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.51-1.550.22771400.18971324X-RAY DIFFRACTION97.6
1.55-1.590.2041410.18261318X-RAY DIFFRACTION99.52
1.59-1.630.21451400.17271333X-RAY DIFFRACTION99.59
1.63-1.690.22771420.18251335X-RAY DIFFRACTION99.73
1.69-1.750.21411430.19311348X-RAY DIFFRACTION99.73
1.75-1.820.24481410.18551325X-RAY DIFFRACTION98.99
1.82-1.90.20951420.18551338X-RAY DIFFRACTION99.6
1.9-20.20751400.18171324X-RAY DIFFRACTION96.89
2-2.130.22261420.19881345X-RAY DIFFRACTION99.8
2.13-2.290.2391440.19421346X-RAY DIFFRACTION99.47
2.29-2.520.22171450.19921368X-RAY DIFFRACTION99.21
2.52-2.890.23541450.20341366X-RAY DIFFRACTION99.08
2.89-3.630.22711440.19351358X-RAY DIFFRACTION97.03
3.63-39.160.18591510.16571428X-RAY DIFFRACTION96.57

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