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

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Basic information

Entry
Database: PDB / ID: 6vub
TitleCrystal structure of BRD4 bromodomain 1 with N-methylpyrrolidin-2-one (NMP) derivative 5 (1-methyl-4-phenylpyrrolidin-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 / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / transcription coactivator activity / positive regulation of canonical NF-kappaB signal transduction / 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-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 / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
(4R)-1-methyl-4-phenylpyrrolidin-2-one / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 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)15,1432
Polymers14,9681
Non-polymers1751
Water4,468248
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 area7480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.619, 44.022, 78.478
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-RLG / (4R)-1-methyl-4-phenylpyrrolidin-2-one


Mass: 175.227 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H13NO / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 248 / 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: 2.17 Å3/Da / Density % sol: 43.34 %
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: MX1 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Nov 5, 2016
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.5→39.24 Å / Num. obs: 21587 / % possible obs: 100 % / Redundancy: 7.9 % / Biso Wilson estimate: 7.59 Å2 / CC1/2: 0.988 / Rmerge(I) obs: 0.177 / Rpim(I) all: 0.097 / Rrim(I) all: 0.202 / Net I/σ(I): 8.6
Reflection shellResolution: 1.5→1.53 Å / Rmerge(I) obs: 1.056 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 1063 / CC1/2: 0.828 / Rpim(I) all: 0.583

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Processing

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

5dw2


Resolution: 1.5→39.24 Å / SU ML: 0.1197 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 16.124
RfactorNum. reflection% reflection
Rfree0.1772 1083 5.03 %
Rwork0.1564 --
obs0.1575 21531 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 12.92 Å2
Refinement stepCycle: LAST / Resolution: 1.5→39.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1048 0 13 248 1309
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061201
X-RAY DIFFRACTIONf_angle_d0.81591653
X-RAY DIFFRACTIONf_chiral_restr0.0443176
X-RAY DIFFRACTIONf_plane_restr0.0054219
X-RAY DIFFRACTIONf_dihedral_angle_d8.3457998
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.570.21071470.18632513X-RAY DIFFRACTION99.96
1.57-1.650.21111400.17432483X-RAY DIFFRACTION100
1.65-1.750.19261170.16572528X-RAY DIFFRACTION99.96
1.75-1.890.20061370.16392521X-RAY DIFFRACTION99.92
1.89-2.080.17581350.15112544X-RAY DIFFRACTION100
2.08-2.380.19321390.1462546X-RAY DIFFRACTION100
2.38-30.18151360.15642585X-RAY DIFFRACTION99.96
3-39.240.1371320.14792728X-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)
12.020248990391.256219592351.423341660895.192927503323.519947602014.232016554620.0575819725560.2177771876910.0404972643478-0.0212711943770.104705454814-0.115020678168-0.1382588682940.1148230661-0.1382041228780.0883772940941-0.008422010315850.01949957523720.1077549733650.03184112911760.05409715852114.31438446046.90383405574-17.2102354155
21.71040408774-1.233899220791.120282394284.235284889-0.06372228761620.838779720285-0.03155536323240.1435055456420.140641531685-0.0665535652826-0.108001206848-0.1384796171630.149740414567-0.1037519255960.1333252633450.2032187223610.01425286765910.04998781505780.09218710687950.0008072710350960.077125603013913.1120878469-8.00412234619-26.4044040411
32.52185326379-1.04447094772-0.03933539151573.47756842838-0.5944926412052.38084378264-0.03159182785130.0888095949335-0.18568823834-0.3501249902410.009167098504590.03545584229160.622635237868-0.4109526411580.06623065110060.146428985978-0.06580291064040.006321510562930.109835441513-0.005995977288650.05226520246286.02287808083-15.1753044283-15.1601813359
40.8867729477350.372440896047-1.457274963196.184414974550.03696192724592.481069278850.0408133021320.138015512684-0.021084738757-0.129870336983-0.02513128025580.2625498284350.0516278664492-0.277317914527-0.06301092682070.029799464364-0.0138895530376-0.001203376751890.0742854209528-0.004347600576360.06501247449223.38015349077-8.5287367065-7.5260784969
52.045661497441.27067659557-0.2545331862972.65927386097-0.3599139877060.7712447794380.00569654907567-0.03842045656910.06041402958660.05548218593660.0006474814770020.0408985540098-0.0255558892702-0.0622948357491-0.003549983747630.02905880530710.007963179821020.007861208950820.0447418342368-0.01514025702330.0360008475388.485996779465.06655957755-1.44489471861
61.833232624041.865221669530.6754226145033.294742856841.51345142272.04284502395-0.09767079438680.107576013362-0.0131488563934-0.1492882044370.0539786227026-0.0194031167859-0.1160224768070.001362914243290.05130475310280.03570319814130.003626344452620.004988483846250.04344254225990.01510645366450.029109199664413.85806126031.65511738907-10.9743504723
70.2632827830250.3486904392650.3838022037132.047355139521.990672498344.378471546760.001442709772990.0515344618973-0.0238470394797-0.02398658364940.032814145942-0.141936237890.09601979040820.0434792710089-0.04737544239240.02932578129510.0003232430518240.008410403224260.04948772611490.00286951856330.049926211387416.4278144517-5.78271044524-10.8681901734
84.52804289877-1.032416598390.0005493218818823.68249738142-4.191937924535.146870366660.0699841765522-0.8285784730450.06938846102690.8181299382950.219709053115-0.2105137001850.02919144281280.733710382513-0.09043558641710.1848089985890.0340717360644-0.02870342863930.220081546588-0.01874501089240.067157911399617.68701141352.617842563188.46910956825
91.336477511860.491095122914-0.4979470307195.557354725842.082922020723.25454323498-0.0348815478443-0.0529202326525-0.05172450612730.260166759870.04550482367950.04758700624910.279520263648-0.0158371737559-0.022046019470.03359024811310.00813498798303-0.008257526459730.05060128498880.01587300624110.049890931620811.3611410635-10.25694991770.538465387338
105.55608659717-2.92531256027-4.259484279986.38319633973.409820311565.408021544140.07483217343921.03222397685-0.226901806615-1.23303275993-0.300803426247-0.03225956311740.365453076369-0.1477102467380.1402941146340.5640300925070.007418658046530.08996336764670.194557664145-0.04541587650840.17681110674610.8237960935-22.3534830452-16.9776266013
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 43 through 52 )
2X-RAY DIFFRACTION2chain 'A' and (resid 53 through 60 )
3X-RAY DIFFRACTION3chain 'A' and (resid 61 through 68 )
4X-RAY DIFFRACTION4chain 'A' and (resid 69 through 75 )
5X-RAY DIFFRACTION5chain 'A' and (resid 76 through 96 )
6X-RAY DIFFRACTION6chain 'A' and (resid 97 through 115 )
7X-RAY DIFFRACTION7chain 'A' and (resid 116 through 139 )
8X-RAY DIFFRACTION8chain 'A' and (resid 140 through 144 )
9X-RAY DIFFRACTION9chain 'A' and (resid 145 through 163 )
10X-RAY DIFFRACTION10chain 'A' and (resid 164 through 168 )

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