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- PDB-6nrh: Crystal Structure of human PARP-1 ART domain bound inhibitor UTT63 -

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Basic information

Entry
Database: PDB / ID: 6nrh
TitleCrystal Structure of human PARP-1 ART domain bound inhibitor UTT63
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


positive regulation of myofibroblast differentiation / regulation of base-excision repair / NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / regulation of circadian sleep/wake cycle, non-REM sleep / vRNA Synthesis ...positive regulation of myofibroblast differentiation / regulation of base-excision repair / NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / regulation of circadian sleep/wake cycle, non-REM sleep / vRNA Synthesis / positive regulation of single strand break repair / carbohydrate biosynthetic process / NAD+-protein-serine ADP-ribosyltransferase activity / regulation of catalytic activity / negative regulation of adipose tissue development / NAD DNA ADP-ribosyltransferase activity / DNA ADP-ribosylation / mitochondrial DNA metabolic process / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / replication fork reversal / ATP generation from poly-ADP-D-ribose / positive regulation of necroptotic process / transcription regulator activator activity / HDR through MMEJ (alt-NHEJ) / positive regulation of DNA-templated transcription, elongation / signal transduction involved in regulation of gene expression / NAD+ ADP-ribosyltransferase / cellular response to zinc ion / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / NAD+-protein-aspartate ADP-ribosyltransferase activity / mitochondrial DNA repair / protein poly-ADP-ribosylation / positive regulation of intracellular estrogen receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / NAD+-protein-glutamate ADP-ribosyltransferase activity / response to aldosterone / positive regulation of mitochondrial depolarization / positive regulation of cardiac muscle hypertrophy / NAD+-protein mono-ADP-ribosyltransferase activity / R-SMAD binding / nuclear replication fork / negative regulation of transcription elongation by RNA polymerase II / protein autoprocessing / site of DNA damage / macrophage differentiation / NAD+ poly-ADP-ribosyltransferase activity / decidualization / Transferases; Glycosyltransferases; Pentosyltransferases / positive regulation of SMAD protein signal transduction / POLB-Dependent Long Patch Base Excision Repair / positive regulation of double-strand break repair via homologous recombination / SUMOylation of DNA damage response and repair proteins / nucleosome binding / protein localization to chromatin / nucleotidyltransferase activity / telomere maintenance / transforming growth factor beta receptor signaling pathway / negative regulation of innate immune response / nuclear estrogen receptor binding / response to gamma radiation / mitochondrion organization / Downregulation of SMAD2/3:SMAD4 transcriptional activity / cellular response to nerve growth factor stimulus / DNA Damage Recognition in GG-NER / protein-DNA complex / protein modification process / positive regulation of protein localization to nucleus / Dual Incision in GG-NER / histone deacetylase binding / Formation of Incision Complex in GG-NER / cellular response to insulin stimulus / cellular response to amyloid-beta / NAD binding / cellular response to UV / nuclear envelope / double-strand break repair / regulation of protein localization / site of double-strand break / cellular response to oxidative stress / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / transcription by RNA polymerase II / damaged DNA binding / positive regulation of canonical NF-kappaB signal transduction / chromosome, telomeric region / nuclear body / innate immune response / DNA repair / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / DNA damage response / chromatin binding / protein kinase binding / chromatin / nucleolus / enzyme binding / negative regulation of transcription by RNA polymerase II / protein homodimerization activity
Similarity search - Function
Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / : / PADR1 domain, zinc ribbon fold / PADR1, N-terminal helical domain / PADR1 domain profile. / PADR1 / Zinc finger poly(ADP-ribose) polymerase (PARP)-type signature. / Zinc finger, PARP-type superfamily ...Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / : / PADR1 domain, zinc ribbon fold / PADR1, N-terminal helical domain / PADR1 domain profile. / 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 / : / Poly(ADP-ribose) polymerase, regulatory domain / WGR domain / WGR domain superfamily / WGR domain / WGR domain profile. / 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-KYP / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.5 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
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)31,0979
Polymers30,0031
Non-polymers1,0948
Water3,801211
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)93.503, 93.503, 137.948
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-KYP / 3-hydroxy-2-({4-[4-(pyrimidin-2-yl)piperazine-1-carbonyl]phenyl}methyl)-1-benzofuran-7-carboxamide


Mass: 457.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H23N5O4
#3: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 211 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.51 Å3/Da / Density % sol: 51.04 %
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: 1.5→47.78 Å / Num. obs: 49081 / % possible obs: 100 % / Redundancy: 24.1 % / CC1/2: 1 / Rmerge(I) obs: 0.041 / Rpim(I) all: 0.008 / Rrim(I) all: 0.041 / Net I/σ(I): 36.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.5-1.5314.71.3623560.7830.361.40899.4
8.22-47.7320.30.03336710.0070.03499.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.5.32data scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDBID 6BHV

6bhv


Resolution: 1.5→47.78 Å / Cor.coef. Fo:Fc: 0.981 / Cor.coef. Fo:Fc free: 0.977 / SU B: 1.941 / SU ML: 0.032 / SU R Cruickshank DPI: 0.0575 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.058 / ESU R Free: 0.053
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.158 2495 5.1 %RANDOM
Rwork0.1291 ---
obs0.1306 46561 99.96 %-
Solvent computationIon probe radii: 0.9 Å / Shrinkage radii: 0.9 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 86.76 Å2 / Biso mean: 32.831 Å2 / Biso min: 19.09 Å2
Baniso -1Baniso -2Baniso -3
1-0.92 Å20 Å20 Å2
2--0.92 Å20 Å2
3----1.84 Å2
Refinement stepCycle: final / Resolution: 1.5→47.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1895 0 67 211 2173
Biso mean--42.22 48 -
Num. residues----240
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0142083
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171951
X-RAY DIFFRACTIONr_angle_refined_deg1.3371.6712828
X-RAY DIFFRACTIONr_angle_other_deg0.9371.6614588
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7025262
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.8922.81296
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.0715388
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6751510
X-RAY DIFFRACTIONr_chiral_restr0.0720.2271
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022403
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02369
X-RAY DIFFRACTIONr_rigid_bond_restr2.22734033
X-RAY DIFFRACTIONr_sphericity_free28.7045122
X-RAY DIFFRACTIONr_sphericity_bonded17.86854073
LS refinement shellResolution: 1.5→1.539 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.275 171 -
Rwork0.224 3388 -
all-3559 -
obs--99.58 %

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