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

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Basic information

Entry
Database: PDB / ID: 6psb
TitleCrystal structure of BRD4 bromodomain 1 with N-methylpyrrolidin-2-one (NMP) derivative 18 (5-{[(3R)-1-methyl-5-oxopyrrolidin-3-yl]methyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one)
ComponentsBromodomain-containing protein 4
KeywordsPROTEIN BINDING / BRD4 BD1 / Bromodomain / Olinone
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 / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / 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 II / Brdt, bromodomain, repeat I / 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-Y18 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.59 Å
AuthorsIlyichova, O.V. / Scanlon, M.J.
CitationJournal: Bioorg.Med.Chem. / Year: 2019
Title: Synthesis and elaboration of N-methylpyrrolidone as an acetamide fragment substitute in bromodomain inhibition.
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
DepositionJul 12, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2019Group: Database references / Category: citation / Item: _citation.journal_volume
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)15,2662
Polymers14,9681
Non-polymers2971
Water3,639202
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 area7360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.614, 52.008, 58.000
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: 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-Y18 / 5-{[(3R)-1-methyl-5-oxopyrrolidin-3-yl]methyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one


Mass: 297.352 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C17H19N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 202 / 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: 2.16 Å3/Da / Density % sol: 43.17 %
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: Jun 21, 2018
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: 1.59→42.61 Å / Num. obs: 17951 / % possible obs: 99.7 % / Redundancy: 7.7 % / Biso Wilson estimate: 13.03 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.032 / Rpim(I) all: 0.018 / Rrim(I) all: 0.037 / Χ2: 1.05 / Net I/σ(I): 39.2
Reflection shellResolution: 1.59→1.62 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.186 / Mean I/σ(I) obs: 9.1 / Num. unique obs: 823 / CC1/2: 0.986 / Rpim(I) all: 0.106 / Rrim(I) all: 0.214 / Χ2: 0.86 / % possible all: 95.1

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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: 1.59→38.72 Å / SU ML: 0.1118 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.9828
RfactorNum. reflection% reflection
Rfree0.209 912 5.1 %
Rwork0.1703 --
obs0.1722 17895 99.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 18.72 Å2
Refinement stepCycle: LAST / Resolution: 1.59→38.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1025 0 22 202 1249
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00781125
X-RAY DIFFRACTIONf_angle_d1.00761547
X-RAY DIFFRACTIONf_chiral_restr0.0451164
X-RAY DIFFRACTIONf_plane_restr0.0053202
X-RAY DIFFRACTIONf_dihedral_angle_d3.35381194
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.59-1.670.2031400.16062329X-RAY DIFFRACTION98.33
1.67-1.780.21611230.16912408X-RAY DIFFRACTION100
1.78-1.910.20591060.18322402X-RAY DIFFRACTION99.88
1.91-2.110.24171230.17222419X-RAY DIFFRACTION99.92
2.11-2.410.21261320.17522417X-RAY DIFFRACTION99.73
2.41-3.040.19621430.18232451X-RAY DIFFRACTION100
3.04-38.720.2051450.15822557X-RAY DIFFRACTION99.82
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)
12.229923625061.86919440922-0.9443022542364.569124093821.532292210546.43968963378-0.08166404914330.05258645639050.152872089476-0.077630167228-0.129427232874-0.1979505419920.1364972967620.01234924225860.1342896924590.1866726254410.0628265808682-0.04092039068740.214078992031-0.06185947627670.23896029959821.239438933-13.3014137932-23.7121435486
23.5572157929-0.38947554201-1.032133206528.23177660886-1.550895175397.969596208350.1718836807270.178228329895-0.299368260973-0.2877301610.07020555030820.1585365221870.1731763321530.35646913159-0.1036934015440.2332330299060.03714141742490.00280872198860.125695170846-0.002832146958050.259411405749.80211161765-6.03933925001-30.0363402201
35.07716189939-0.7985959067610.1893425946522.30039193523-0.2667038739821.07889398214-0.1349033096570.626215915493-0.156643045244-0.129755621106-0.03633095545710.1519542909440.0709588614126-0.1638511105530.01549079938160.134086659088-0.00577767658731-0.005439745403030.1420901242070.002247469081730.0982925831164-0.536371596243-0.96928246756-32.2504699106
41.65208642649-0.659913886580.1887674808412.18883396107-0.08159217380422.27579215032-0.154488685931-0.158172642236-0.1588110046360.2557994330620.1324667927810.191530250491-0.032797854174-0.0430255972113-0.003095358352050.09775596617770.01220895054130.01524752304070.09480864620040.01831364675180.101581541273-3.862794579330.513240224611-18.8499934229
54.9998065169-0.5055931387190.6482170835690.06035039305150.1114275760073.05463391315-0.07746616345420.04831124309710.3591381060760.1343248256820.156351683354-0.286423572952-0.36889159136-0.454363319025-0.1113730694050.1169247553840.0261104030586-0.005502930629980.09275589247150.01715523915330.164080625973.55718499805-0.519501049127-12.0365359965
61.159962333480.535121827694-0.2658445230651.212431030780.1009710050992.033319618980.0694542935963-0.1959454505880.1396290348270.09383233067140.131433389182-0.2403225104180.01846147873140.36859939161-0.1038294557850.1149586540350.00480467865125-0.02594088121310.137580218128-0.02181069888480.11193682118816.3557134264-9.42992106124-9.64176615195
71.51777180795-0.6256948755650.3987961895360.852033176901-0.6533844833311.59927752566-0.01168422980890.0203603491688-0.02121580534-0.0510397231586-0.00299199999190.02414482931460.1414922857980.03897337803780.01593006052120.101720999342-0.006516740476360.01018877960750.0864516151557-0.008332361137740.08022669658668.70381254138-9.62600888988-21.6685242856
80.87182393944-0.957814594670.1156684423661.9805024294-0.818319321821.63056193611-0.02112611791970.05357163881890.00167356627356-0.02402702305540.04868164586430.1159935253320.02390784650170.00250928339797-0.0640193218960.0987843541712-0.01341687053860.005404187763460.08838305152950.0005704327876330.0909447980864.89378637789-14.8664123085-15.3306620499
91.672138091372.862307651170.7389817283065.48139275487-0.6145309201286.490687693750.170703821037-0.458353383606-0.1904769750.319240040284-0.1569732069680.07897953715650.3671825825120.233119172482-0.08622266865590.1105595248910.00786496993455-0.0056039167040.1745958665210.03741898465350.11494048378413.4991210796-20.6039603422-2.29281152221
104.32014117466-0.8716337342191.429565580631.78184352451-0.7741567782422.12588645171-0.0160159798729-0.1169152653590.2512174549860.0757189850970.08987166090750.109820350448-0.0946587305295-0.236355929468-0.06854394488530.11851473849-0.004634637946730.0254333517390.1119355541280.008656915864960.100434063822-0.347847094884-9.29983882733-7.72573573167
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 43 through 47 )
2X-RAY DIFFRACTION2chain 'A' and (resid 48 through 52 )
3X-RAY DIFFRACTION3chain 'A' and (resid 53 through 60 )
4X-RAY DIFFRACTION4chain 'A' and (resid 61 through 68 )
5X-RAY DIFFRACTION5chain 'A' and (resid 69 through 75 )
6X-RAY DIFFRACTION6chain 'A' and (resid 76 through 96 )
7X-RAY DIFFRACTION7chain 'A' and (resid 97 through 121 )
8X-RAY DIFFRACTION8chain 'A' and (resid 122 through 139 )
9X-RAY DIFFRACTION9chain 'A' and (resid 140 through 144 )
10X-RAY DIFFRACTION10chain 'A' and (resid 145 through 167 )

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