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

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Basic information

Entry
Database: PDB / ID: 8pxm
TitleN-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH (1R,1'R)-7,7'-(pentane-1,5-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-ZTY / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.378 Å
AuthorsChung, C.W.
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 1.0Oct 4, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,7354
Polymers30,1992
Non-polymers5372
Water3,747208
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5742
Polymers15,0991
Non-polymers4751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,1612
Polymers15,0991
Non-polymers621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.936, 59.766, 105.287
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: 15099.380 Da / Num. of mol.: 2
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-ZTY / (1R)-7-[5-[[(1R)-1,3-dimethyl-2-oxidanylidene-1H-3-benzazepin-7-yl]oxy]pentoxy]-1,3-dimethyl-1H-3-benzazepin-2-one / (1R,1'R)-7,7'-(pentane-1,5-diylbis(oxy))bis(1,3-dimethyl-1,3-dihydro-2H-benzo[d]azepin-2-one)


Mass: 474.591 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H34N2O4
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 208 / 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: 2.18 Å3/Da / Density % sol: 43.7 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 0.1M Tris pH8.5, 0.2M lithium sulphate, 16% w/v PEG4K

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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: Jul 27, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.38→41.94 Å / Num. obs: 7281 / % possible obs: 91.9 % / Redundancy: 2.1 % / CC1/2: 0.923 / Rmerge(I) obs: 0.047 / Net I/av σ(I): 14.5 / Net I/σ(I): 14.5
Reflection shellResolution: 2.38→2.75 Å / Redundancy: 2 % / Rmerge(I) obs: 0.116 / Mean I/σ(I) obs: 6.8 / Num. unique obs: 3638 / CC1/2: 0.686 / % possible all: 96.1

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.378→39.5 Å / Cor.coef. Fo:Fc: 0.912 / Cor.coef. Fo:Fc free: 0.827 / SU R Cruickshank DPI: 1.498 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.394 / SU Rfree Cruickshank DPI: 0.377
RfactorNum. reflection% reflectionSelection details
Rfree0.3093 506 -RANDOM
Rwork0.207 ---
obs0.2122 9811 87.8 %-
Displacement parametersBiso mean: 16.76 Å2
Baniso -1Baniso -2Baniso -3
1--3.6512 Å20 Å20 Å2
2--3.2214 Å20 Å2
3---0.4298 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: LAST / Resolution: 2.378→39.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2122 0 39 208 2369
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0072240HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.833050HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d775SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes367HARMONIC5
X-RAY DIFFRACTIONt_it2240HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion283SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2029SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.44
X-RAY DIFFRACTIONt_other_torsion17.67
LS refinement shellResolution: 2.38→2.41 Å
RfactorNum. reflection% reflection
Rfree0.3836 19 -
Rwork0.2228 --
obs0.2295 393 93.47 %

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