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- PDB-6nrj: Crystal Structure of human PARP-1 ART domain bound to inhibitor UTT93 -

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Basic information

Entry
Database: PDB / ID: 6nrj
TitleCrystal Structure of human PARP-1 ART domain bound to inhibitor UTT93
ComponentsPoly [ADP-ribose] polymerase 1
Keywordstransferase/transferase inhibitor / PARP-1 / poly(ADP-ribose) polymerase / PARP inhibitor / PARP1 / ARTD1 / TRANSFERASE / transferase-transferase inhibitor complex
Function / homology
Function and homology information


NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / regulation of base-excision repair / positive regulation of myofibroblast differentiation / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / negative regulation of ATP biosynthetic process / carbohydrate biosynthetic process / regulation of circadian sleep/wake cycle, non-REM sleep ...NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / regulation of base-excision repair / positive regulation of myofibroblast differentiation / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / negative regulation of ATP biosynthetic process / carbohydrate biosynthetic process / regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of single strand break repair / vRNA Synthesis / NAD+-protein-serine ADP-ribosyltransferase activity / negative regulation of adipose tissue development / NAD DNA ADP-ribosyltransferase activity / NAD+- protein-aspartate ADP-ribosyltransferase activity / NAD+-protein-glutamate ADP-ribosyltransferase activity / DNA ADP-ribosylation / mitochondrial DNA metabolic process / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / signal transduction involved in regulation of gene expression / replication fork reversal / positive regulation of necroptotic process / ATP generation from poly-ADP-D-ribose / regulation of catalytic activity / HDR through MMEJ (alt-NHEJ) / transcription regulator activator activity / : / positive regulation of DNA-templated transcription, elongation / NAD+ ADP-ribosyltransferase / cellular response to zinc ion / negative regulation of telomere maintenance via telomere lengthening / positive regulation of intracellular estrogen receptor signaling pathway / protein auto-ADP-ribosylation / positive regulation of mitochondrial depolarization / response to aldosterone / mitochondrial DNA repair / negative regulation of cGAS/STING signaling pathway / positive regulation of double-strand break repair via homologous recombination / protein poly-ADP-ribosylation / positive regulation of cardiac muscle hypertrophy / nuclear replication fork / negative regulation of transcription elongation by RNA polymerase II / site of DNA damage / NAD+-protein ADP-ribosyltransferase activity / R-SMAD binding / positive regulation of SMAD protein signal transduction / macrophage differentiation / protein autoprocessing / decidualization / NAD+ ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / nucleosome binding / POLB-Dependent Long Patch Base Excision Repair / SUMOylation of DNA damage response and repair proteins / protein localization to chromatin / telomere maintenance / negative regulation of innate immune response / mitochondrion organization / nucleotidyltransferase activity / cellular response to nerve growth factor stimulus / transforming growth factor beta receptor signaling pathway / nuclear estrogen receptor binding / protein-DNA complex / response to gamma radiation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / DNA Damage Recognition in GG-NER / protein modification process / Dual Incision in GG-NER / Formation of Incision Complex in GG-NER / positive regulation of protein localization to nucleus / histone deacetylase binding / cellular response to insulin stimulus / cellular response to amyloid-beta / cellular response to UV / NAD binding / regulation of protein localization / double-strand break repair / site of double-strand break / nuclear envelope / cellular response to oxidative stress / positive regulation of canonical NF-kappaB signal transduction / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / transcription by RNA polymerase II / damaged DNA binding / chromosome, telomeric region / nuclear body / DNA repair / innate immune response / negative regulation of DNA-templated transcription / apoptotic process / DNA damage response / chromatin binding / ubiquitin protein ligase binding / chromatin / nucleolus / protein kinase binding / negative regulation of transcription by RNA polymerase II / enzyme binding
Similarity search - Function
: / PADR1, N-terminal helical domain / PADR1 domain profile. / Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / PADR1 domain, zinc ribbon fold / PADR1 / Zinc finger poly(ADP-ribose) polymerase (PARP)-type signature. / Zinc finger, PARP-type superfamily ...: / PADR1, N-terminal helical domain / PADR1 domain profile. / Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / PADR1 domain, zinc ribbon fold / PADR1 / Zinc finger poly(ADP-ribose) polymerase (PARP)-type signature. / Zinc finger, PARP-type superfamily / Poly(ADP-ribose) polymerase and DNA-Ligase Zn-finger region / Zinc finger poly(ADP-ribose) polymerase (PARP)-type profile. / Poly(ADP-ribose) polymerase and DNA-Ligase Zn-finger region / Zinc finger, PARP-type / WGR domain profile. / Poly(ADP-ribose) polymerase, regulatory domain / WGR domain / WGR domain superfamily / WGR domain / Proposed nucleic acid binding domain / Poly(ADP-ribose) polymerase, regulatory domain superfamily / Poly(ADP-ribose) polymerase, regulatory domain / PARP alpha-helical domain profile. / Phosphoenolpyruvate Carboxykinase; domain 3 - #10 / Phosphoenolpyruvate Carboxykinase; domain 3 / BRCA1 C Terminus (BRCT) domain / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. / breast cancer carboxy-terminal domain / BRCT domain profile. / BRCT domain / BRCT domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-KYJ / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.65 Å
AuthorsLangelier, M.F. / Pascal, J.M.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)BMA342854 Canada
CitationJournal: J.Med.Chem. / Year: 2019
Title: Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
Authors: Velagapudi, U.K. / Langelier, M.F. / Delgado-Martin, C. / Diolaiti, M.E. / Bakker, S. / Ashworth, A. / Patel, B.A. / Shao, X. / Pascal, J.M. / Talele, T.T.
History
DepositionJan 23, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
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

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Assembly

Deposited unit
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,0929
Polymers30,0031
Non-polymers1,0898
Water2,288127
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)94.465, 94.465, 137.627
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number98
Space group name H-MI4122

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Components

#1: Protein Poly [ADP-ribose] polymerase 1 / PARP-1 / ADP-ribosyltransferase diphtheria toxin-like 1 / ARTD1 / NAD(+) ADP-ribosyltransferase 1 / ...PARP-1 / ADP-ribosyltransferase diphtheria toxin-like 1 / ARTD1 / NAD(+) ADP-ribosyltransferase 1 / ADPRT 1 / Poly[ADP-ribose] synthase 1


Mass: 30003.275 Da / Num. of mol.: 1 / Fragment: ADP-ribosyltransferase (ART) domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1, ADPRT, PPOL / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2(DE3)
References: UniProt: P09874, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Chemical ChemComp-KYJ / (2Z)-2-[(4-{[2-(1H-benzimidazol-2-yl)ethyl]carbamoyl}phenyl)methylidene]-3-oxo-2,3-dihydro-1-benzofuran-7-carboxamide


Mass: 452.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H20N4O4
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 127 / 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: 2.56 Å3/Da / Density % sol: 51.92 % / Mosaicity: 0.2 °
Crystal growTemperature: 298 K / Method: evaporation / pH: 7.5
Details: ~20% PEG 3350, 0.2 M ammonium sulfate or sodium citrate, 100 mM Hepes pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 8, 2018
RadiationMonochromator: ACCEL/BRUKER double crystal monochromator (DCM), Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.65→47.98 Å / Num. obs: 37738 / % possible obs: 100 % / Redundancy: 27.8 % / CC1/2: 1 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.015 / Rrim(I) all: 0.078 / Net I/σ(I): 22.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.65-1.6826.81.7385139219160.7490.3341.7711.699.8
8.89-47.9323.10.042689229910.0090.04361.199.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.6.2data scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDBID 6BHV

6bhv


Resolution: 1.65→47.98 Å / Cor.coef. Fo:Fc: 0.974 / Cor.coef. Fo:Fc free: 0.967 / SU B: 2.955 / SU ML: 0.051 / SU R Cruickshank DPI: 0.0788 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.079 / ESU R Free: 0.078
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.1913 1975 5.3 %RANDOM
Rwork0.1677 ---
obs0.1689 35588 99.58 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1.3 Å
Displacement parametersBiso max: 111.72 Å2 / Biso mean: 34.032 Å2 / Biso min: 19.66 Å2
Baniso -1Baniso -2Baniso -3
1-0.41 Å20 Å20 Å2
2--0.41 Å20 Å2
3----0.83 Å2
Refinement stepCycle: final / Resolution: 1.65→47.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1895 0 67 127 2089
Biso mean--47.71 40.24 -
Num. residues----240
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0142032
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171883
X-RAY DIFFRACTIONr_angle_refined_deg1.2621.6662753
X-RAY DIFFRACTIONr_angle_other_deg0.9071.6614414
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.715248
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.98123.3792
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.50515365
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.515158
X-RAY DIFFRACTIONr_chiral_restr0.0650.2263
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022362
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02362
LS refinement shellResolution: 1.65→1.693 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.259 144 -
Rwork0.251 2601 -
all-2745 -
obs--99.96 %
Refinement TLS params.Method: refined / Origin x: 25.8222 Å / Origin y: -4.3905 Å / Origin z: 18.6381 Å
111213212223313233
T0.0365 Å20.0065 Å2-0.0096 Å2-0.0139 Å2-0.0023 Å2--0.0152 Å2
L2.7226 °20.6322 °2-1.2522 °2-1.1132 °2-0.4423 °2--1.7046 °2
S-0.0581 Å °0.0659 Å °0.04 Å °0.0592 Å °0.0316 Å °0.0915 Å °-0.0762 Å °-0.1466 Å °0.0265 Å °

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