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- PDB-5ha9: Crystal structure-based design and disovery of a novel PARP1 anti... -

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Basic information

Entry
Database: PDB / ID: 5ha9
TitleCrystal structure-based design and disovery of a novel PARP1 antiagonist (BL-PA10) that induces apoptosis and inhibits metastasis in triple negative breast cancer
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTransferase/Transferase inhibitor / inhibitor / 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 / 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 / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / carbohydrate biosynthetic process / regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of single strand break repair / vRNA Synthesis / negative regulation of adipose tissue development / NAD+-protein-serine ADP-ribosyltransferase activity / NAD DNA ADP-ribosyltransferase activity / NAD+- protein-aspartate ADP-ribosyltransferase activity / NAD+-protein-glutamate ADP-ribosyltransferase activity / mitochondrial DNA metabolic process / DNA ADP-ribosylation / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / signal transduction involved in regulation of gene expression / positive regulation of necroptotic process / regulation of catalytic activity / ATP generation from poly-ADP-D-ribose / replication fork reversal / transcription regulator activator activity / HDR through MMEJ (alt-NHEJ) / 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 / positive regulation of mitochondrial depolarization / response to aldosterone / mitochondrial DNA repair / 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 / R-SMAD binding / site of DNA damage / positive regulation of SMAD protein signal transduction / protein autoprocessing / macrophage differentiation / decidualization / Transferases; Glycosyltransferases; Pentosyltransferases / positive regulation of double-strand break repair via homologous recombination / NAD+ ADP-ribosyltransferase activity / POLB-Dependent Long Patch Base Excision Repair / SUMOylation of DNA damage response and repair proteins / nucleosome binding / protein localization to chromatin / negative regulation of innate immune response / telomere maintenance / nucleotidyltransferase activity / mitochondrion organization / transforming growth factor beta receptor signaling pathway / cellular response to nerve growth factor stimulus / nuclear estrogen receptor binding / response to gamma radiation / protein-DNA complex / 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 / histone deacetylase binding / positive regulation of protein localization to nucleus / cellular response to amyloid-beta / cellular response to insulin stimulus / regulation of protein localization / cellular response to UV / NAD binding / double-strand break repair / nuclear envelope / site of double-strand break / cellular response to oxidative stress / positive regulation of canonical NF-kappaB signal transduction / RNA polymerase II-specific DNA-binding transcription factor binding / transcription regulator complex / 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 / ubiquitin protein ligase binding / DNA damage response / chromatin binding / chromatin / nucleolus / protein kinase binding / enzyme binding / negative regulation of transcription by RNA polymerase II / protein homodimerization activity
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. / 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
Similarity search - Domain/homology
Amitriptyline / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 4.01 Å
AuthorsFu, L. / Peng, H. / Zhang, L. / Ouyang, L.
CitationJournal: Sci Rep / Year: 2016
Title: Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer.
Authors: Fu, L. / Wang, S. / Wang, X. / Wang, P. / Zheng, Y. / Yao, D. / Guo, M. / Zhang, L. / Ouyang, L.
History
DepositionDec 30, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Mar 9, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2017Group: Database references
Revision 1.2Jul 11, 2018Group: Data collection / Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Mar 20, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Poly [ADP-ribose] polymerase 1
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,69411
Polymers78,6562
Non-polymers1,0389
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2780 Å2
ΔGint-77 kcal/mol
Surface area31850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.000, 92.431, 162.932
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 39328.055 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 662-1011
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1 / Production host: Escherichia coli K-12 (bacteria) / Strain (production host): K-12 / References: UniProt: P09874, NAD+ ADP-ribosyltransferase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-TP0 / Amitriptyline / 3-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene)-N,N-dimethylpropan-1-amine


Mass: 277.403 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23N / Comment: antidepressant*YM

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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: 2.3 Å3/Da / Density % sol: 46.47 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.2 / Details: 2.1 M AMMONIUM SULFATE, 100mM TRIS

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Data collection

DiffractionMean temperature: 193 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 1.006323 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jan 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.006323 Å / Relative weight: 1
ReflectionResolution: 4→50 Å / Num. obs: 6434 / % possible obs: 99.1 % / Redundancy: 4.5 % / Rmerge(I) obs: 0.212 / Χ2: 2.04 / Net I/av σ(I): 9.947 / Net I/σ(I): 6.2 / Num. measured all: 29162
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
4-4.074.80.3982921.962100
4.07-4.144.70.4373221.9499.7
4.14-4.224.70.3493042.106100
4.22-4.314.50.3483252.20798.5
4.31-4.44.50.2913072.57798.4
4.4-4.54.80.2863132.17999.4
4.5-4.624.60.2533202.324100
4.62-4.744.60.2583192.24999.7
4.74-4.884.60.243152.41199.4
4.88-5.044.70.2383062.12399.7
5.04-5.224.60.2673231.94799.7
5.22-5.434.40.2563241.9399.1
5.43-5.674.70.2973181.897100
5.67-5.974.40.2723311.68999.7
5.97-6.354.50.2553101.60698.4
6.35-6.844.10.2183361.57399.7
6.84-7.524.70.143201.59199.7
7.52-8.64.50.1093411.78499.7
8.6-10.824.40.0823422.1299.4
10.82-503.80.0863662.65193.8

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.15data extraction
MOLREPphasing
RefinementResolution: 4.01→50 Å / Cor.coef. Fo:Fc: 0.888 / Cor.coef. Fo:Fc free: 0.73 / SU B: 101.143 / SU ML: 1.276 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 1.399 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3578 300 4.7 %RANDOM
Rwork0.2421 ---
obs0.2475 6104 98.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 146.39 Å2 / Biso mean: 76.293 Å2 / Biso min: 52.94 Å2
Baniso -1Baniso -2Baniso -3
1--2.41 Å20 Å2-0 Å2
2--9.27 Å2-0 Å2
3----6.87 Å2
Refinement stepCycle: final / Resolution: 4.01→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5501 0 63 0 5564
Biso mean--111.58 --
Num. residues----702
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0195662
X-RAY DIFFRACTIONr_bond_other_d0.0020.025495
X-RAY DIFFRACTIONr_angle_refined_deg0.8681.9937649
X-RAY DIFFRACTIONr_angle_other_deg0.6923.00112706
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3965700
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.94625.146239
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.127151037
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6841522
X-RAY DIFFRACTIONr_chiral_restr0.0470.2862
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0216293
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021195
X-RAY DIFFRACTIONr_mcbond_it1.2637.6752806
X-RAY DIFFRACTIONr_mcbond_other1.2627.6742805
X-RAY DIFFRACTIONr_mcangle_it2.33411.5083504
LS refinement shellResolution: 4.007→4.111 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 16 -
Rwork0.212 369 -
all-385 -
obs--87.3 %

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