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- PDB-3l3l: PARP complexed with A906894 -

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Basic information

Entry
Database: PDB / ID: 3l3l
TitlePARP complexed with A906894
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTransferase/Transferase Inhibitor / Protein-Inhibitor Complex / ADP-ribosylation / DNA damage / DNA repair / DNA-binding / Glycosyltransferase / Metal-binding / NAD / Nucleus / Phosphoprotein / Transcription / Transcription regulation / 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 / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / carbohydrate biosynthetic process / positive regulation of single strand break repair ...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 / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / carbohydrate biosynthetic process / positive regulation of single strand break repair / regulation of circadian sleep/wake cycle, non-REM sleep / vRNA Synthesis / negative regulation of adipose tissue development / NAD+-protein-serine ADP-ribosyltransferase activity / regulation of catalytic activity / 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 / positive regulation of necroptotic process / ATP generation from poly-ADP-D-ribose / replication fork reversal / transcription regulator activator activity / HDR through MMEJ (alt-NHEJ) / R-SMAD binding / positive regulation of DNA-templated transcription, elongation / positive regulation of intracellular estrogen receptor signaling pathway / NAD+ ADP-ribosyltransferase / cellular response to zinc ion / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / response to aldosterone / mitochondrial DNA repair / positive regulation of mitochondrial depolarization / negative regulation of cGAS/STING signaling pathway / protein poly-ADP-ribosylation / positive regulation of cardiac muscle hypertrophy / negative regulation of transcription elongation by RNA polymerase II / nuclear replication fork / NAD+-protein ADP-ribosyltransferase activity / site of DNA damage / positive regulation of SMAD protein signal transduction / macrophage differentiation / protein autoprocessing / decidualization / NAD+-protein poly-ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / positive regulation of double-strand break repair via homologous recombination / POLB-Dependent Long Patch Base Excision Repair / nucleosome binding / SUMOylation of DNA damage response and repair proteins / protein localization to chromatin / negative regulation of innate immune response / telomere maintenance / nucleotidyltransferase activity / transforming growth factor beta receptor signaling pathway / cellular response to nerve growth factor stimulus / mitochondrion organization / 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 / cellular response to insulin stimulus / Dual Incision in GG-NER / histone deacetylase binding / Formation of Incision Complex in GG-NER / positive regulation of protein localization to nucleus / cellular response to amyloid-beta / nuclear envelope / NAD binding / regulation of protein localization / cellular response to UV / double-strand break repair / site of double-strand break / positive regulation of canonical NF-kappaB signal transduction / cellular response to oxidative stress / chromosome, telomeric region / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / transcription by RNA polymerase II / damaged DNA binding / nuclear body / DNA repair / innate immune response / negative regulation of DNA-templated transcription / chromatin binding / DNA damage response / ubiquitin protein ligase binding / chromatin / nucleolus / protein kinase binding / apoptotic process / enzyme binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II
Similarity search - Function
Poly(ADP-ribose) polymerase, regulatory domain / Poly(ADP-ribose) Polymerase; domain 1 / : / PADR1, N-terminal helical domain / PADR1 domain profile. / Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / PADR1 domain, zinc ribbon fold / PADR1 ...Poly(ADP-ribose) polymerase, regulatory domain / Poly(ADP-ribose) Polymerase; domain 1 / : / 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 / Up-down Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-L3L / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsPark, C.H.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer.
Authors: Gandhi, V.B. / Luo, Y. / Liu, X. / Shi, Y. / Klinghofer, V. / Johnson, E.F. / Park, C. / Giranda, V.L. / Penning, T.D. / Zhu, G.D.
History
DepositionDec 17, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.4Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)39,4282
Polymers39,1691
Non-polymers2591
Water1,44180
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Poly [ADP-ribose] polymerase 1
hetero molecules
x 6


Theoretical massNumber of molelcules
Total (without water)236,56912
Polymers235,0136
Non-polymers1,5566
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_675-y+1,x-y+2,z1
crystal symmetry operation3_465-x+y-1,-x+1,z1
crystal symmetry operation4_466y-1,x+1,-z+11
crystal symmetry operation5_676x-y+1,-y+2,-z+11
crystal symmetry operation6_556-x,-x+y,-z+11
Buried area15810 Å2
ΔGint-57 kcal/mol
Surface area83890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.023, 94.023, 68.773
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number150
Space group name H-MP321

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Components

#1: Protein Poly [ADP-ribose] polymerase 1 / PARP-1 / ADPRT / NAD(+) ADP-ribosyltransferase 1 / Poly[ADP-ribose] synthetase 1


Mass: 39168.809 Da / Num. of mol.: 1 / Fragment: residues 662-1011 / Mutation: V762A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1, ADPRT, PPOL / Production host: Escherichia coli (E. coli) / References: UniProt: P09874, NAD+ ADP-ribosyltransferase
#2: Chemical ChemComp-L3L / 3-oxo-2-piperidin-4-yl-2,3-dihydro-1H-isoindole-4-carboxamide


Mass: 259.304 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H17N3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / 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: 2.24 Å3/Da / Density % sol: 45.1 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Protein Solution : PARP 60 mg/ml in 50 mM Tris, 150 mM NaCl, 1.5 mM DTT PH 7.5, 2mM A861146 Well Solution : 0.8 M NaCl, 1.8 M Ammonium Sulfate Crystals are soaked in well solution containing ...Details: Protein Solution : PARP 60 mg/ml in 50 mM Tris, 150 mM NaCl, 1.5 mM DTT PH 7.5, 2mM A861146 Well Solution : 0.8 M NaCl, 1.8 M Ammonium Sulfate Crystals are soaked in well solution containing 1mM A906894 from 0.1 M DMSO stock Cryoprotectant : 1.2 M NaCl, 1.6 M Ammonium Sulfate, 20 % Ethylene Glycol, VAPOR DIFFUSION, HANGING DROP, temperature 290K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 13, 2005
RadiationMonochromator: Not sure / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→81.4 Å / Num. all: 12539 / Num. obs: 12000 / % possible obs: 95.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.8 % / Biso Wilson estimate: 19.7 Å2 / Rsym value: 0.111 / Net I/σ(I): 7.6
Reflection shellResolution: 2.5→2.65 Å / Redundancy: 4 % / Mean I/σ(I) obs: 2.2 / Num. unique all: 1633 / Rsym value: 0.74 / % possible all: 95.7

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Processing

Software
NameClassification
HKL-2000data collection
CNSrefinement
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Inhouse PARP-A904051 structure

Resolution: 2.5→40.71 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 98569.83 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.285 583 5.1 %RANDOM
Rwork0.21 ---
all0.214 12539 --
obs0.214 12000 95.7 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 46.044 Å2 / ksol: 0.35 e/Å3
Displacement parametersBiso mean: 47.6 Å2
Baniso -1Baniso -2Baniso -3
1--11.42 Å20 Å20 Å2
2---11.42 Å20 Å2
3---22.83 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.33 Å0.34 Å
Luzzati d res low-5 Å
Luzzati sigma a0.38 Å0.44 Å
Refinement stepCycle: LAST / Resolution: 2.5→40.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2751 0 19 80 2850
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d26.7
X-RAY DIFFRACTIONc_improper_angle_d2.19
X-RAY DIFFRACTIONc_mcbond_it3.171.5
X-RAY DIFFRACTIONc_mcangle_it3.962
X-RAY DIFFRACTIONc_scbond_it7.542
X-RAY DIFFRACTIONc_scangle_it9.82.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.5→2.65 Å / Rfactor Rfree error: 0.043 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.34 84 4.4 %
Rwork0.248 1341 -
obs-1633 68.4 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramlig.top
X-RAY DIFFRACTION3ion.param
X-RAY DIFFRACTION4lig.par

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