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- PDB-8pxn: N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH (1R,1'R)-7,7'-(ethane-1... -

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Basic information

Entry
Database: PDB / ID: 8pxn
TitleN-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH (1R,1'R)-7,7'-(ethane-1,2-diylbis(oxy))bis(1,3-dimethyl-1,3-dihydro-2H-benzo[d]azepin-2-one)
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / INHIBITOR / HISTONE / EPIGENETIC READER / BROMODOMAIN / BRD4 / BROMODOMAIN CONTAINING PROTEIN 4 / ANTAGONIST
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 / chromatin / 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, conserved site / Bromodomain signature. ...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, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-ZTT / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.952 Å
AuthorsChung, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Design and Characterization of 1,3-Dihydro-2 H -benzo[ d ]azepin-2-ones as Rule-of-5 Compliant Bivalent BET Inhibitors.
Authors: Bamborough, P. / Chung, C.W. / Goodwin, N.C. / Mitchell, D.J. / Neipp, C.E. / Phillipou, A. / Preston, A. / Prinjha, R.K. / Soden, P.E. / Watson, R.J. / Demont, E.H.
History
DepositionJul 23, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: Bromodomain-containing protein 4
C: Bromodomain-containing protein 4
D: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,3878
Polymers60,3984
Non-polymers9894
Water13,872770
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5943
Polymers15,0991
Non-polymers4952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bromodomain-containing protein 4


Theoretical massNumber of molelcules
Total (without water)15,0991
Polymers15,0991
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Bromodomain-containing protein 4


Theoretical massNumber of molelcules
Total (without water)15,0991
Polymers15,0991
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5943
Polymers15,0991
Non-polymers4952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)30.265, 41.879, 105.383
Angle α, β, γ (deg.)89.973, 89.948, 89.882
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 15099.380 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-ZTT / (1R)-7-[2-[[(1R)-1,3-dimethyl-2-oxidanylidene-1H-3-benzazepin-7-yl]oxy]ethoxy]-1,3-dimethyl-1H-3-benzazepin-2-one / (1R,1'R)-7,7'-(ethane-1,2-diylbis(oxy))bis(1,3-dimethyl-1,3-dihydro-2H-benzo[d]azepin-2-one)


Mass: 432.512 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28N2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 770 / 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: 2.21 Å3/Da / Density % sol: 44.38 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 0.1M Tris pH8.5, 12% w/v 4K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN A200 / Detector: CCD / Date: Sep 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
Reflection twin
TypeCrystal-IDIDOperatorDomain-IDFraction
pseudo-merohedral11H, K, L10.3049
pseudo-merohedral22-h,-k,l20.2772
pseudo-merohedral33-H, K, -L30.2154
pseudo-merohedral44h,-k,-l40.2025
ReflectionResolution: 1.95→52.69 Å / Num. obs: 35040 / % possible obs: 92.8 % / Redundancy: 2.1 % / CC1/2: 0.975 / Rmerge(I) obs: 0.043 / Net I/σ(I): 18.3
Reflection shellResolution: 1.95→2.18 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.128 / Mean I/σ(I) obs: 6.7 / Num. unique obs: 9779 / CC1/2: 0.878 / % possible all: 90.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.952→35.128 Å / Cor.coef. Fo:Fc: 0.899 / Cor.coef. Fo:Fc free: 0.826 / SU B: 5.719 / SU ML: 0.17 / Cross valid method: FREE R-VALUE / ESU R: 0.045 / ESU R Free: 0.046
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2701 1609 4.728 %
Rwork0.192 32422 -
all0.196 --
obs-34031 90.388 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL PLUS MASK
Displacement parametersBiso mean: 16.077 Å2
Baniso -1Baniso -2Baniso -3
1-0.145 Å2-2.068 Å28.773 Å2
2--4.455 Å2-3.615 Å2
3----4.601 Å2
Refinement stepCycle: LAST / Resolution: 1.952→35.128 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4226 0 72 770 5068
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0124420
X-RAY DIFFRACTIONr_bond_other_d0.0020.0164020
X-RAY DIFFRACTIONr_angle_refined_deg1.4031.6726011
X-RAY DIFFRACTIONr_angle_other_deg0.4541.5759454
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0875501
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.068512
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.62510786
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.43510215
X-RAY DIFFRACTIONr_chiral_restr0.0630.2634
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024783
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02789
X-RAY DIFFRACTIONr_nbd_refined0.2410.21300
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1990.24387
X-RAY DIFFRACTIONr_nbtor_refined0.1890.22146
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0760.22245
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2590.2501
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0760.26
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1730.235
X-RAY DIFFRACTIONr_nbd_other0.190.2107
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2490.237
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0470.21
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.952-2.0030.341010.232057X-RAY DIFFRACTION75.7991
2.003-2.0580.305940.1252368X-RAY DIFFRACTION90.648
2.058-2.1170.2381120.1212201X-RAY DIFFRACTION90.281
2.117-2.1820.2061370.1972237X-RAY DIFFRACTION90.3349
2.182-2.2540.4421160.4422034X-RAY DIFFRACTION87.4339
2.254-2.3330.413950.3861931X-RAY DIFFRACTION81.9911
2.333-2.4210.2071010.1521983X-RAY DIFFRACTION93.411
2.421-2.520.276500.1312020X-RAY DIFFRACTION91.4311
2.52-2.6320.293900.1281897X-RAY DIFFRACTION92.7638
2.632-2.760.2971010.1371808X-RAY DIFFRACTION93.3496
2.76-2.910.239850.1371682X-RAY DIFFRACTION92.6586
2.91-3.0860.179680.1321691X-RAY DIFFRACTION94.4683
3.086-3.2990.197790.1261540X-RAY DIFFRACTION93.9095
3.299-3.5630.192590.1611459X-RAY DIFFRACTION93.8195
3.563-3.9020.366600.2391305X-RAY DIFFRACTION92.4171
3.902-4.3620.193910.1551199X-RAY DIFFRACTION95.5556
4.362-5.0360.183450.1621048X-RAY DIFFRACTION94.4685
5.036-6.1640.231610.175898X-RAY DIFFRACTION95.6132
6.164-8.7020.319470.189678X-RAY DIFFRACTION94.8953
8.702-35.1280.301170.167386X-RAY DIFFRACTION95.2719

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