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- PDB-6vuc: Crystal structure of BRD4 bromodomain 1 with N-methylpyrrolidin-2... -

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Basic information

Entry
Database: PDB / ID: 6vuc
TitleCrystal structure of BRD4 bromodomain 1 with N-methylpyrrolidin-2-one (NMP) derivative 7b (1-methyl-4-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-one)
ComponentsBromodomain-containing protein 4
KeywordsPROTEIN BINDING / BRD4 BD1 / Bromodomain / NMP
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-like / Histone Acetyltransferase; Chain A ...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-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-RLS / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsIlyichova, O.V. / Scanlon, M.J. / Thompson, P.E.
CitationJournal: Eur.J.Med.Chem. / Year: 2020
Title: Substituted 1-methyl-4-phenylpyrrolidin-2-ones - Fragment-based design of N-methylpyrrolidone-derived bromodomain inhibitors.
Authors: Hilton-Proctor, J.P. / Ilyichova, O. / Zheng, Z. / Jennings, I.G. / Johnstone, R.W. / Shortt, J. / Mountford, S.J. / Scanlon, M.J. / Thompson, P.E.
History
DepositionFeb 14, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 26, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 18, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,2912
Polymers14,9681
Non-polymers3221
Water4,216234
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.744, 48.942, 61.184
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 14968.182 Da / Num. of mol.: 1 / Fragment: bromodomain 1 (UNP residues 44-168)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pET28(a) / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: O60885
#2: Chemical ChemComp-RLS / (4R)-1-methyl-4-{4-[(piperidin-1-yl)sulfonyl]phenyl}pyrrolidin-2-one


Mass: 322.422 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H22N2O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 234 / 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: 2.19 Å3/Da / Density % sol: 43.78 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: 0.2 M sodium nitrate, 35% PEG3350, 6% v/v ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.95372 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 27, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95372 Å / Relative weight: 1
ReflectionResolution: 1.55→43.74 Å / Num. obs: 19456 / % possible obs: 98.9 % / Redundancy: 13.4 % / Biso Wilson estimate: 10.18 Å2 / CC1/2: 0.985 / Rmerge(I) obs: 0.158 / Rpim(I) all: 0.063 / Net I/σ(I): 10.4
Reflection shellResolution: 1.55→1.58 Å / Rmerge(I) obs: 0.864 / Mean I/σ(I) obs: 2.9 / Num. unique obs: 959 / CC1/2: 0.889 / Rpim(I) all: 0.361

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5DW2

5dw2


Resolution: 1.55→38.22 Å / SU ML: 0.1552 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.838
RfactorNum. reflection% reflection
Rfree0.2115 967 4.98 %
Rwork0.1677 --
obs0.1699 19416 98.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 16.61 Å2
Refinement stepCycle: LAST / Resolution: 1.55→38.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1043 0 22 235 1300
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00761155
X-RAY DIFFRACTIONf_angle_d0.92961591
X-RAY DIFFRACTIONf_chiral_restr0.0492170
X-RAY DIFFRACTIONf_plane_restr0.0056208
X-RAY DIFFRACTIONf_dihedral_angle_d2.6812972
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.55-1.630.25771300.19862588X-RAY DIFFRACTION97.45
1.63-1.730.24271450.18182536X-RAY DIFFRACTION97.85
1.73-1.870.28751300.18572591X-RAY DIFFRACTION98.27
1.87-2.060.23341310.16742620X-RAY DIFFRACTION98.67
2.06-2.350.18011260.16542646X-RAY DIFFRACTION98.93
2.35-2.960.22171590.16632643X-RAY DIFFRACTION99.36
2.96-38.220.17581460.15542825X-RAY DIFFRACTION99.93
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.94045950720.0614585142350.2632593600811.15309945773-0.9693901488071.43798170821-0.185028321328-0.23704391311-0.386194550750.0706546653020.142224744927-0.162866444347-0.02119249670336.85995354735E-50.0450406513310.1060140638360.02940150705880.009119056299330.09178342249810.0173842465060.107570015672-8.26423746399-7.3214449621532.2944202494
25.5512611742-1.846822653123.115708919542.05167959975-1.744635746854.40737710188-0.1499225920950.04560506913560.1257441130330.0113964770836-0.063459752154-0.22812781648-0.3249596096040.3705930579740.2006827105030.0871844552031-0.0287102906163-0.002502923395240.09845405429640.01926052976920.1252566615054.221427998331.9429070494223.5854922033
31.443703540060.229182966978-0.4647775062432.26864689651-0.250556707681.75163345363-0.1060334835140.194111864218-0.0266866897749-0.09389109183440.09591814299520.1797377663160.0687035521527-0.2552678157620.01005937124840.0568212133449-0.0162174045930.001655012581890.07840140101170.008001983435220.0510013339157-13.5971740891-5.6396002297914.7923022089
43.34610600075-0.8104818110892.108570382581.43866497263-0.6814991379182.68168025599-0.0768727375384-0.321375972150.114102831190.03657363023560.0458051309832-0.13940716382-0.1015362770840.022204059580.02253811611490.05087670711170.006053942619060.01163296494150.08670209516270.004693384859860.0569494058275-2.76692514682-3.6073933223129.4095964214
53.16046305951.003295265712.220303551281.499829876981.014981457714.309050534830.0143255067371-0.0199835778391-0.161014931532-0.06551571188580.00195489856252-0.1256793347410.240361815820.143126129103-0.04952815266790.06821075304770.02525632040610.0356774262650.04512503523980.01746017083630.0597219845574-2.95650018199-10.61159830417.4836764512
64.113148461230.1473308634430.4888688458671.8318682341-0.3232503136062.20721718404-0.01444613931490.3482300077070.0569171297162-0.352953165988-0.0393920980095-0.2024525846480.1614888133290.431010861912-0.01951274660520.1042936573060.02122699011640.05870863912260.1085475039060.0259014047850.0860678979580.31853780018-5.108685472479.28232965949
78.51005740966-0.7415381572182.617441618172.760080468260.9715845678346.91686549194-0.0274563523355-0.331047281332-0.1610875107650.206484244439-0.0915572065535-0.4883632998060.02970404238340.1404477706470.0477301699170.137624390350.000517020067058-0.01273897583460.3627424137230.1235529067070.35664826295315.0578212396-3.8068828018327.0038164173
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 43 through 60 )
2X-RAY DIFFRACTION2chain 'A' and (resid 61 through 76 )
3X-RAY DIFFRACTION3chain 'A' and (resid 77 through 106 )
4X-RAY DIFFRACTION4chain 'A' and (resid 107 through 121 )
5X-RAY DIFFRACTION5chain 'A' and (resid 122 through 139 )
6X-RAY DIFFRACTION6chain 'A' and (resid 140 through 162 )
7X-RAY DIFFRACTION7chain 'A' and (resid 163 through 168 )

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