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- PDB-6nri: Crystal Structure of human PARP-1 ART domain bound to inhibitor UTT83 -

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Basic information

Entry
Database: PDB / ID: 6nri
TitleCrystal Structure of human PARP-1 ART domain bound to inhibitor UTT83
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 / HDR through MMEJ (alt-NHEJ) / ATP generation from poly-ADP-D-ribose / regulation of catalytic activity / 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 / mitochondrion organization / telomere maintenance / negative regulation of innate immune response / 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 / cellular response to oxidative stress / nuclear envelope / 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 / chromosome, telomeric region / damaged DNA binding / 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 / enzyme binding / negative regulation of transcription by RNA polymerase II
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
CITRIC ACID / Chem-KYM / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 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)30,7645
Polymers30,0031
Non-polymers7614
Water1,00956
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)92.616, 92.616, 142.072
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number98
Space group name H-MI4122

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Components

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Protein , 1 types, 1 molecules A

#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

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Non-polymers , 5 types, 60 molecules

#2: Chemical ChemComp-KYM / (2Z)-2-{[4-(3-cyclopropyl-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carbonyl)phenyl]methylidene}-3-oxo-2,3-dihydro-1-benzofuran-7-carboxamide


Mass: 455.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H21N5O4
#3: Chemical ChemComp-CIT / CITRIC ACID / Citric acid


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 56 / 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: 2.54 Å3/Da / Density % sol: 51.55 % / Mosaicity: 0.17 °
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: 2.2→48.2 Å / Num. obs: 16019 / % possible obs: 99.9 % / Redundancy: 15.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.081 / Rpim(I) all: 0.021 / Rrim(I) all: 0.084 / Net I/σ(I): 20.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.2-2.2716.21.18913310.8330.3031.22798.7
9.08-48.1511.50.0492760.9990.0150.05199.2

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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: 2.2→48.2 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.947 / SU B: 11.229 / SU ML: 0.139 / SU R Cruickshank DPI: 0.2204 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.22 / ESU R Free: 0.194
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2375 821 5.1 %RANDOM
Rwork0.1849 ---
obs0.1876 15182 99.93 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1 Å
Displacement parametersBiso max: 118.3 Å2 / Biso mean: 56.441 Å2 / Biso min: 37.57 Å2
Baniso -1Baniso -2Baniso -3
1-0.96 Å20 Å20 Å2
2--0.96 Å20 Å2
3----1.92 Å2
Refinement stepCycle: final / Resolution: 2.2→48.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1898 0 52 56 2006
Biso mean--73.26 53.73 -
Num. residues----241
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0142003
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171847
X-RAY DIFFRACTIONr_angle_refined_deg1.3411.6642710
X-RAY DIFFRACTIONr_angle_other_deg0.861.6644332
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2235243
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.24723.29791
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.49715354
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.459158
X-RAY DIFFRACTIONr_chiral_restr0.0630.2255
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022329
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02355
LS refinement shellResolution: 2.202→2.259 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.391 52 -
Rwork0.351 1094 -
all-1146 -
obs--99.48 %
Refinement TLS params.Method: refined / Origin x: 25.1952 Å / Origin y: -4.5335 Å / Origin z: 20.062 Å
111213212223313233
T0.0905 Å20.0057 Å2-0.041 Å2-0.0351 Å2-0.0112 Å2--0.0271 Å2
L4.1997 °20.5821 °2-1.7386 °2-1.5617 °2-0.7043 °2--2.603 °2
S-0.0693 Å °0.1619 Å °-0.0114 Å °0.0646 Å °-0.0027 Å °0.0659 Å °-0.0968 Å °-0.2809 Å °0.072 Å °

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