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- PDB-6u0d: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Entry
Database: PDB / ID: 6u0d
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor ZL0590
ComponentsBromodomain-containing protein 4BRD4
KeywordsGENE REGULATION / Bromodomain / Inhibitor / Complex
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 / 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-POJ / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.43 Å
AuthorsLeonard, P.G. / Joseph, S.
Funding support United States, 1items
OrganizationGrant numberCountry
Crohns and Colitis Foundation576144 United States
CitationJournal: J. Med. Chem. / Year: 2022
Title: Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site
Authors: Liu, Z. / Li, Y. / Chen, H. / Lai, H. / Wang, P. / Wu, S. / Wold, E.A. / Leonard, P.G. / Joseph, S. / Hu, H. / Chiang, C. / Brasier, A.R. / Tian, B. / Zhou, J.
History
DepositionAug 14, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 2.0Jan 19, 2022Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / citation ...atom_site / citation / citation_author / database_2 / entity_src_gen / pdbx_contact_author / pdbx_nonpoly_scheme / refine / refine_hist / refine_ls_shell / reflns / reflns_shell / software / struct_site / struct_site_gen
Item: _atom_site.Cartn_x / _atom_site.Cartn_y ..._atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.gene_src_common_name / _pdbx_contact_author.id / _pdbx_nonpoly_scheme.auth_mon_id / _pdbx_nonpoly_scheme.auth_seq_num / _refine.B_iso_mean / _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.ls_R_factor_obs / _refine.ls_d_res_high / _refine.ls_d_res_low / _refine.ls_number_reflns_R_work / _refine_hist.d_res_high / _refine_hist.d_res_low / _refine_ls_shell.d_res_high / _refine_ls_shell.d_res_low / _reflns.pdbx_number_measured_all / _reflns.pdbx_scaling_rejects / _software.classification / _software.name / _software.version
Description: Ligand geometry
Details: The inhibitor, ZL0590, was associated with the binding site of a symmetry related protomer in the crystal lattice. This structure changes the coordinates for the ZL0590 inhibitor so that it ...Details: The inhibitor, ZL0590, was associated with the binding site of a symmetry related protomer in the crystal lattice. This structure changes the coordinates for the ZL0590 inhibitor so that it is in the binding site that agrees with the structure activity relationship for this compound series.
Provider: author / Type: Coordinate replacement
Revision 2.1Oct 11, 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)15,6903
Polymers15,0991
Non-polymers5912
Water3,333185
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Protein elutes from a gel filtration column as a monomer.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.470, 42.380, 80.290
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Bromodomain-containing protein 4 / BRD4 / 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-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-POJ / N-[4-({(2S)-2-[(morpholin-4-yl)methyl]pyrrolidin-1-yl}sulfonyl)phenyl]-N'-[4-(trifluoromethyl)phenyl]urea


Mass: 512.545 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27F3N4O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 185 / 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: 2.11 Å3/Da / Density % sol: 41.73 % / Description: Orthorhombic
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 100 mM HEPES, 15% PEG 3350 at pH 7.5 / Temp details: Room temperature

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1.00018 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 9, 2019
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00018 Å / Relative weight: 1
ReflectionResolution: 1.429→33.954 Å / Num. obs: 24020 / % possible obs: 98.7 % / Redundancy: 4.7 % / CC1/2: 0.989 / Rmerge(I) obs: 0.167 / Rpim(I) all: 0.084 / Rrim(I) all: 0.188 / Net I/σ(I): 5.3 / Num. measured all: 110290 / Scaling rejects: 712
Reflection shellResolution: 1.43→1.45 Å / Redundancy: 4.7 % / Rmerge(I) obs: 2.225 / Mean I/σ(I) obs: 1.3 / Num. measured all: 5602 / Num. unique obs: 1197 / CC1/2: 0.437 / Rpim(I) all: 1.096 / Rrim(I) all: 2.494 / Net I/σ(I) obs: 1.3 / % possible all: 99.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation4.62 Å33.95 Å
Translation4.62 Å33.95 Å

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Processing

Software
NameVersionClassification
iMOSFLM7.2.2data reduction
Aimless0.7.4data scaling
PHASER2.8.2phasing
PHENIX1.16-3549refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5KU3

5ku3


Resolution: 1.43→33.95 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 23.43
RfactorNum. reflection% reflection
Rfree0.223 1995 8.35 %
Rwork0.185 21887 -
obs0.188 23882 97.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 50.56 Å2 / Biso mean: 20.72 Å2 / Biso min: 9.67 Å2
Refinement stepCycle: final / Resolution: 1.43→33.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1052 0 39 185 1276
Biso mean--30.26 30.44 -
Num. residues----126
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.43-1.46480.32871410.2976154798
1.4648-1.50440.3351390.2771152898
1.5044-1.54860.29621380.2439151397
1.5486-1.59860.29671410.2297154698
1.5986-1.65570.26621420.2235155297
1.6557-1.7220.27631410.2178154698
1.722-1.80040.27251420.197155899
1.8004-1.89530.24971450.1997157899
1.8953-2.0140.21341430.1877157899
2.014-2.16950.23041410.179155598
2.1695-2.38780.20121420.1853154696
2.3878-2.73320.22191460.18351601100
2.7332-3.4430.21631480.167162399
3.443-33.950.1751460.1518161693

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