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- PDB-4lrg: Structure of BRD4 bromodomain 1 with a dimethyl thiophene isoxazo... -

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Basic information

Entry
Database: PDB / ID: 4lrg
TitleStructure of BRD4 bromodomain 1 with a dimethyl thiophene isoxazole azepine carboxamide
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION REGULATOR/INHIBITOR / BET inhibitor / Brd4 first bromodomain / TRANSCRIPTION REGULATOR-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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader 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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader 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 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like ...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-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-1XB / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.21 Å
AuthorsRavichandran, S. / Jayaram, H. / Poy, F. / Gehling, V. / Hewitt, M. / Vaswani, R. / Leblanc, Y. / Cote, A. / Nasveschuk, C. / Taylor, A. ...Ravichandran, S. / Jayaram, H. / Poy, F. / Gehling, V. / Hewitt, M. / Vaswani, R. / Leblanc, Y. / Cote, A. / Nasveschuk, C. / Taylor, A. / Harmange, J.-C. / Audia, J. / Pardo, E. / Joshi, S. / Sandy, P. / Mertz, J. / Sims, R. / Bergeron, L. / Bryant, B. / Yellapuntala, S. / Nandana, B.S. / Birudukota, S. / Albrecht, B. / Bellon, S.
CitationJournal: ACS Med Chem Lett / Year: 2013
Title: Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.
Authors: Gehling, V.S. / Hewitt, M.C. / Vaswani, R.G. / Leblanc, Y. / Cote, A. / Nasveschuk, C.G. / Taylor, A.M. / Harmange, J.C. / Audia, J.E. / Pardo, E. / Joshi, S. / Sandy, P. / Mertz, J.A. / ...Authors: Gehling, V.S. / Hewitt, M.C. / Vaswani, R.G. / Leblanc, Y. / Cote, A. / Nasveschuk, C.G. / Taylor, A.M. / Harmange, J.C. / Audia, J.E. / Pardo, E. / Joshi, S. / Sandy, P. / Mertz, J.A. / Sims, R.J. / Bergeron, L. / Bryant, B.M. / Bellon, S. / Poy, F. / Jayaram, H. / Sankaranarayanan, R. / Yellapantula, S. / Bangalore Srinivasamurthy, N. / Birudukota, S. / Albrecht, B.K.
History
DepositionJul 19, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 14, 2013Group: Other / Structure summary
Revision 1.2Oct 8, 2014Group: Database references
Revision 1.3Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)15,5262
Polymers15,1261
Non-polymers4001
Water1,946108
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.044, 45.604, 78.581
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 / Protein HUNK1


Mass: 15126.339 Da / Num. of mol.: 1 / Fragment: bromodomain 1 (UNP residues 42-168)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, BRD4_HUMAN, HUNK1 / Plasmid: pRSF / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: O60885
#2: Chemical ChemComp-1XB / 2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-[1,2]oxazolo[5,4-c]thieno[2,3-e]azepin-6-yl]acetamide


Mass: 399.894 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18ClN3O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 108 / Source method: isolated from a natural source / Formula: H2O

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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: 2.13 Å3/Da / Density % sol: 42.38 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1M Bis-Tris pH 7.0, 150mM NaCl, 25% PEG3350. Cryo used: 23% Glycerol in well solution, temperature 278K, VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jul 20, 2012 / Details: Osmics VariMax HR
RadiationMonochromator: CONFOCAL MIRROR MICROMAX / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.21→50 Å / Num. obs: 6843 / % possible obs: 99 % / Redundancy: 7 % / Rmerge(I) obs: 0.067 / Χ2: 1.065 / Net I/σ(I): 12.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.21-2.295.60.2966031.159190.3
2.29-2.386.60.2846771.181199.9
2.38-2.497.10.2516581.2091100
2.49-2.627.20.1956861.1341100
2.62-2.787.30.1466841.1231100
2.78-37.40.1056771.1561100
3-3.37.30.0746911.0621100
3.3-3.787.30.05269011100
3.78-4.767.20.0387020.8691100
4.76-506.70.0367750.825199.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
PHASERphasing
REFMAC5.7.0024refinement
PDB_EXTRACT3.11data extraction
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.21→39.44 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.908 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 10.282 / SU ML: 0.247 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.435 / ESU R Free: 0.28 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2879 326 4.8 %RANDOM
Rwork0.2267 ---
obs0.2298 6808 99.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 86.85 Å2 / Biso mean: 39.662 Å2 / Biso min: 13.02 Å2
Baniso -1Baniso -2Baniso -3
1-3.28 Å20 Å20 Å2
2---1.17 Å20 Å2
3----2.11 Å2
Refinement stepCycle: LAST / Resolution: 2.21→39.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1065 0 27 108 1200
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0221130
X-RAY DIFFRACTIONr_bond_other_d0.0010.021046
X-RAY DIFFRACTIONr_angle_refined_deg1.3482.0011545
X-RAY DIFFRACTIONr_angle_other_deg0.75332423
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3855129
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.3725.92654
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.9415196
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.63153
X-RAY DIFFRACTIONr_chiral_restr0.0610.2162
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211305
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02242
LS refinement shellResolution: 2.215→2.272 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.478 23 -
Rwork0.341 442 -
all-465 -
obs--92.08 %

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