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- PDB-7uzn: CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPL... -

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Entry
Database: PDB / ID: 7uzn
TitleCRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH BMT-206059 AKA 2-{(3M)-3-(1,4-DIMETHYL-1H-1,2,3-TRIAZOL-5-YL)-8-FLUORO-5-[(S)-(OXAN-4-YL)(PHENYL)METHYL]-5H-PYRIDO[3,2-b]INDOL-7-YL}PROPAN-2-OL, TRIPLY DEUTERATED ON THE 4-METHYL GROUP
ComponentsBromodomain-containing protein 4
KeywordsCELL CYCLE / BROMODOMAIN-CONTAINING PROTEIN 4 ISOFORM LONG / BRD4 / BROMODOMAIN CONTAINING PROTEIN 4 / CAP / HUNK1 / MCAP / MITOTIC CHROMOSOME ASSOCIATED PROTEIN
Function / homologyAmanitin/phalloidin toxin / toxin activity / Chem-PQF / Alpha-amanitin proprotein 1
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.685 Å
AuthorsSheriff, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Development of BET Inhibitors as Potential Treatments for Cancer: Optimization of Pharmacokinetic Properties.
Authors: Hill, M.D. / Fang, H. / Norris, D. / Delucca, G.V. / Huang, H. / DeBenedetto, M. / Quesnelle, C. / Schmitz, W.D. / Tokarski, J.S. / Sheriff, S. / Yan, C. / Fanslau, C. / Haarhoff, Z. / ...Authors: Hill, M.D. / Fang, H. / Norris, D. / Delucca, G.V. / Huang, H. / DeBenedetto, M. / Quesnelle, C. / Schmitz, W.D. / Tokarski, J.S. / Sheriff, S. / Yan, C. / Fanslau, C. / Haarhoff, Z. / Huang, C. / Kramer, M. / Madari, S. / Menard, K. / Monereau, L. / Morrison, J. / Raghavan, N. / Shields, E.E. / Simmermacher-Mayer, J. / Sinz, M. / Tye, C.K. / Westhouse, R. / Xie, C. / Zhang, H. / Zhang, L. / Zvyaga, T. / Lee, F. / Gavai, A.V. / Degnan, A.P.
History
DepositionMay 9, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 17, 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)15,8685
Polymers15,2071
Non-polymers6614
Water1,17165
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.549, 46.168, 58.745
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 15207.499 Da / Num. of mol.: 1 / Fragment: first bromodomain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: PET28 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O60885
#2: Chemical ChemComp-PQF / 2-{(3M)-3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol


Mass: 513.606 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H32FN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 65 / 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: 1.85 Å3/Da / Density % sol: 33.6 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 100 mM bis-tris propane, pH 8.5, 200 mM NaNO3, 20.5%(w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.685→36.299 Å / Num. obs: 10718 / % possible obs: 92.8 % / Redundancy: 5.44 %
Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last ...Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last updated 2020-04-13: http://mmcif.wwpdb.org/dictionaries/mmcif_pdbx_v50.dic/Index/) and the actual quantities provided by MRFANA (https://github.com/githubgphl/MRFANA) from the autoPROC package (https://www.globalphasing.com/autoproc/). In general, the mmCIF categories here should provide items that are currently used in the PDB archive. If there are alternatives, the one recommended by the PDB developers has been selected. The distinction between *_all and *_obs quantities is not always clear: often only one version is actively used within the PDB archive (or is the one recommended by PDB developers). The intention of distinguishing between classes of reflections before and after some kind of observation criterion was applied, can in principle be useful - but such criteria change in various ways throughout the data processing steps (rejection of overloaded or too partial reflections, outlier/misfit rejections during scaling etc) and there is no retrospect computation of data scaling/merging statistics for the reflections used in the final refinement (where another observation criterion might have been applied). Typical data processing will usually only provide one version of statistics at various stages and these are given in the recommended item here, irrespective of the "_all" and "_obs" connotation, see e.g. the use of _reflns.pdbx_Rmerge_I_obs, _reflns.pdbx_Rrim_I_all and _reflns.pdbx_Rpim_I_all. Please note that all statistics related to "merged intensities" (or "merging") are based on inverse-variance weighting of the individual measurements making up a symmetry-unique reflection. This is standard for several decades now, even if some of the dictionary definitions seem to suggest that a simple "mean" or "average" intensity is being used instead. R-values are always given for all symmetry-equivalent reflections following Friedel's law, i.e. Bijvoet pairs are not treated separately (since we want to describe the overall mean intensity and not the mean I(+) and I(-) here). The Rrim metric is identical to the Rmeas R-value and only differs in name. _reflns.pdbx_number_measured_all is the number of measured intensities just before the final merging step (at which point no additional rejection takes place). _reflns.number_obs is the number of symmetry-unique observations, i.e. the result of merging those measurements via inverse-variance weighting. _reflns.pdbx_netI_over_sigmaI is based on the merged intensities (_reflns.number_obs) as expected. _reflns.pdbx_redundancy is synonymous with "multiplicity". The per-shell item _reflns_shell.number_measured_all corresponds to the overall value _reflns.pdbx_number_measured_all. The per-shell item _reflns_shell.number_unique_all corresponds to the overall value _reflns.number_obs. The per-shell item _reflns_shell.percent_possible_all corresponds to the overall value _reflns.percent_possible_obs. The per-shell item _reflns_shell.meanI_over_sigI_obs corresponds to the overall value given as _reflns.pdbx_netI_over_sigmaI. But be aware of the incorrect definition of the former in the current dictionary!
CC1/2: 0.998 / CC1/2 anomalous: -0.177 / Rmerge(I) obs: 0.1121 / Rpim(I) all: 0.0522 / Rrim(I) all: 0.124 / AbsDiff over sigma anomalous: 0.711 / Baniso tensor eigenvalue 1: 0 Å2 / Baniso tensor eigenvalue 2: 6.8773 Å2 / Baniso tensor eigenvalue 3: 6.1214 Å2 / Baniso tensor eigenvector 1 ortho1: 1 / Baniso tensor eigenvector 1 ortho2: 0 / Baniso tensor eigenvector 1 ortho3: 0 / Baniso tensor eigenvector 2 ortho1: 0 / Baniso tensor eigenvector 2 ortho2: 1 / Baniso tensor eigenvector 2 ortho3: 0 / Baniso tensor eigenvector 3 ortho1: 0 / Baniso tensor eigenvector 3 ortho2: 0 / Baniso tensor eigenvector 3 ortho3: 1 / Aniso diffraction limit 1: 1.656 Å / Aniso diffraction limit 2: 1.872 Å / Aniso diffraction limit 3: 1.776 Å / Aniso diffraction limit axis 1 ortho1: 1 / Aniso diffraction limit axis 1 ortho2: 0 / Aniso diffraction limit axis 1 ortho3: 0 / Aniso diffraction limit axis 2 ortho1: 0 / Aniso diffraction limit axis 2 ortho2: 1 / Aniso diffraction limit axis 2 ortho3: 0 / Aniso diffraction limit axis 3 ortho1: 0 / Aniso diffraction limit axis 3 ortho2: 0 / Aniso diffraction limit axis 3 ortho3: 1 / Net I/σ(I): 8.99 / Num. measured all: 58348 / Observed signal threshold: 1.2 / Orthogonalization convention: pdb / % possible anomalous: 92 / % possible ellipsoidal: 92.8 / % possible ellipsoidal anomalous: 92 / % possible spherical: 80.6 / % possible spherical anomalous: 79.4 / Redundancy anomalous: 2.95 / Signal type: local
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2CC1/2 anomalousRpim(I) allRrim(I) allAbsDiff over sigma anomalous% possible anomalous% possible ellipsoidal% possible ellipsoidal anomalous% possible spherical% possible spherical anomalousRedundancy anomalous% possible all
5.113-36.29950.049724.85267826785365360.999-0.3040.02380.05540.67299.799.699.799.699.73.0499.6
4.026-5.1135.170.047624.54276727675355350.998-0.2020.02270.05290.68999.599.899.599.899.52.9499.8
3.489-4.0265.620.054723.23301130115365360.998-0.4010.02490.06020.6799.810099.810099.83.11100
3.155-3.4895.520.069619.05296129615365360.9960.0340.03190.07680.7111001001001001003.04100
2.922-3.1555.320.096714.62284928495365360.993-0.020.0460.10740.7499.510099.510099.52.91100
2.742-2.9225.710.129412.24305530555355350.9920.0250.05920.14260.7331001001001001003.09100
2.596-2.7425.790.161310.14310731075375370.9930.0320.07280.17730.7451001001001001003.1100
2.482-2.5965.440.1918.75291329135355350.982-0.1720.08880.21120.71399.310099.310099.32.95100
2.385-2.4825.30.23167.03284228425365360.969-0.010.11030.25740.72699.810099.810099.82.87100
2.299-2.3855.460.2815.92292929295365360.961-0.0460.13060.31060.72399.810099.810099.82.93100
2.226-2.2995.530.27546297129715375370.966-0.0640.12740.3040.73299.899.899.899.899.82.9499.8
2.161-2.2265.60.35594.83300230025365360.938-0.0740.16370.39250.73199.810099.810099.82.99100
2.101-2.1615.70.41174.26305330535365360.932-0.1140.18740.45320.71699.810099.810099.83.01100
2.049-2.1015.310.48153.49284528455365360.892-0.1050.22670.53380.71199.810099.810099.82.88100
2.001-2.0495.420.61742.74290029005355350.796-0.1150.28940.68350.72399.410099.410099.42.87100
1.957-25.460.77832.2292029205355350.812-0.1360.36070.85990.70299.210099.210099.22.93100
1.914-1.9575.660.91271.92303730375375370.68-0.0020.41531.00470.73195.894.295.894.295.82.9894.2
1.873-1.9145.661.11131.54302830285355350.616-0.1240.50541.22330.67486.886.486.886.486.83.0186.4
1.825-1.8735.61.27981.3300430045365360.6130.0020.58281.40930.6978.679.578.671.471.42.9679.5
1.685-1.8254.611.14681.29247624765375370.548-0.1470.56681.28480.67346.548.246.519.318.52.5148.2

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Processing

Software
NameVersionClassification
autoPROC1.1.7 20220203data processing
autoPROCJan 26, 2018data processing
Aimless0.7.4data scaling
STARANISO2.3.82data scaling
BUSTER2.11.8 (3-FEB-2022)refinement
XDS20180808data reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3UVW

3uvw


Resolution: 1.685→16.96 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.947 / SU R Cruickshank DPI: 0.285 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.163 / SU Rfree Blow DPI: 0.131 / SU Rfree Cruickshank DPI: 0.129
RfactorNum. reflection% reflectionSelection details
Rfree0.2169 471 -RANDOM
Rwork0.1968 ---
obs0.1977 10700 80.6 %-
Displacement parametersBiso mean: 23.64 Å2
Baniso -1Baniso -2Baniso -3
1--0.1259 Å20 Å20 Å2
2---0.0892 Å20 Å2
3---0.2151 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: LAST / Resolution: 1.685→16.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1032 0 47 65 1144
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082193HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.823976HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d622SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes353HARMONIC5
X-RAY DIFFRACTIONt_it1130HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion138SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies3HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact1755SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.15
X-RAY DIFFRACTIONt_other_torsion14.28
LS refinement shellResolution: 1.69→1.82 Å
RfactorNum. reflection% reflection
Rfree0.26 18 -
Rwork0.267 --
obs0.2667 466 17.74 %

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