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- PDB-8wy7: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 8wy7
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 22
ComponentsBromodomain-containing protein 4
KeywordsPROTEIN BINDING / BRD4(1) / Bromodomain
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / host-mediated suppression of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / histone reader activity / : ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / host-mediated suppression of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / histone reader activity / : / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / positive regulation of canonical NF-kappaB signal transduction / transcription coactivator activity / 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, conserved site ...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, conserved site / Bromodomain signature. / Bromodomain / Bromodomain (BrD) profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-XHN / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.83 Å
AuthorsXu, H. / Zhao, X. / Shen, H. / Xu, Y. / Wu, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)22307116 China
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.
Authors: Jiang, W. / Hou, Q. / Xu, H. / Yang, K. / Wang, X. / Zhang, K. / Zeng, Y. / Li, W. / Wang, B. / Luo, G. / Zhao, X. / Shen, H. / Xu, Y. / Wu, X.
History
DepositionOct 30, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 24, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)51,9576
Polymers50,3023
Non-polymers1,6553
Water724
1
A: Bromodomain-containing protein 4
C: Bromodomain-containing protein 4
hetero molecules

B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,9576
Polymers50,3023
Non-polymers1,6553
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_554-y,-x,-z-1/61
Unit cell
Length a, b, c (Å)140.150, 140.150, 134.299
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

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


Mass: 16767.326 Da / Num. of mol.: 3
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-XHN / 2-[[5-[2-(4-fluoranyl-2,6-dimethyl-phenoxy)-5-(2-oxidanylpropan-2-yl)phenyl]-1-methyl-2-oxidanylidene-pyridin-4-yl]amino]-~{N}-(4-oxidanylcyclohexyl)ethanamide


Mass: 551.649 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C31H38FN3O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 3.78 Å3/Da / Density % sol: 67.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 2.0 M Sodium formate, 0.1 M Tris pH 8.5

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 16, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.83→134.3 Å / Num. obs: 18153 / % possible obs: 94.7 % / Redundancy: 17.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.208 / Rpim(I) all: 0.052 / Rrim(I) all: 0.214 / Net I/σ(I): 20 / Num. measured all: 317495
Reflection shellResolution: 2.83→2.98 Å / % possible obs: 100 % / Redundancy: 20.7 % / Rmerge(I) obs: 0.949 / Num. measured all: 56702 / Num. unique obs: 2736 / CC1/2: 0.803 / Rpim(I) all: 0.204 / Rrim(I) all: 0.971 / Net I/σ(I) obs: 2.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
Aimlessdata scaling
XDSdata reduction
MERLOTphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.83→121.37 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.913 / SU B: 12.414 / SU ML: 0.241 / Cross valid method: THROUGHOUT / ESU R: 0.421 / ESU R Free: 0.335 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28074 884 4.9 %RANDOM
Rwork0.20494 ---
obs0.20842 17230 94.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 88.464 Å2
Baniso -1Baniso -2Baniso -3
1--0.64 Å2-0.32 Å2-0 Å2
2---0.64 Å2-0 Å2
3---2.08 Å2
Refinement stepCycle: 1 / Resolution: 2.83→121.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2731 0 120 4 2855
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.022932
X-RAY DIFFRACTIONr_bond_other_d0.0040.022698
X-RAY DIFFRACTIONr_angle_refined_deg1.872.0013994
X-RAY DIFFRACTIONr_angle_other_deg1.1243.0136281
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4565320
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.89925.603141
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.94415513
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.392157
X-RAY DIFFRACTIONr_chiral_restr0.0910.2421
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0213129
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02576
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it6.9158.6921298
X-RAY DIFFRACTIONr_mcbond_other6.9128.6941299
X-RAY DIFFRACTIONr_mcangle_it9.59713.0351612
X-RAY DIFFRACTIONr_mcangle_other9.59513.0371613
X-RAY DIFFRACTIONr_scbond_it7.1499.1811634
X-RAY DIFFRACTIONr_scbond_other7.1469.1821635
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other10.36113.5342383
X-RAY DIFFRACTIONr_long_range_B_refined12.6696.6943412
X-RAY DIFFRACTIONr_long_range_B_other12.65996.7063413
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.83→2.904 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.236 65 -
Rwork0.243 1314 -
obs--100 %

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