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- PDB-5xst: novel orally efficacious inhibitors complexed with PARP1 -

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Basic information

Entry
Database: PDB / ID: 5xst
Titlenovel orally efficacious inhibitors complexed with PARP1
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / complex structure / 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 / positive regulation of myofibroblast differentiation / regulation of base-excision repair / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / positive regulation of single strand break repair / 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 / positive regulation of myofibroblast differentiation / regulation of base-excision repair / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / positive regulation of single strand break repair / regulation of circadian sleep/wake cycle, non-REM sleep / vRNA Synthesis / carbohydrate biosynthetic process / NAD+-protein-serine ADP-ribosyltransferase activity / regulation of catalytic 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 / replication fork reversal / signal transduction involved in regulation of gene expression / positive regulation of necroptotic process / ATP generation from poly-ADP-D-ribose / transcription regulator activator activity / HDR through MMEJ (alt-NHEJ) / negative regulation of cGAS/STING signaling pathway / 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 / mitochondrial DNA repair / response to aldosterone / protein poly-ADP-ribosylation / positive regulation of mitochondrial depolarization / positive regulation of cardiac muscle hypertrophy / nuclear replication fork / negative regulation of transcription elongation by RNA polymerase II / NAD+-protein ADP-ribosyltransferase activity / site of DNA damage / R-SMAD binding / positive regulation of SMAD protein signal transduction / protein autoprocessing / macrophage differentiation / decidualization / NAD+-protein poly-ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / nucleosome binding / 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 / negative regulation of innate immune response / protein localization to chromatin / telomere maintenance / nucleotidyltransferase activity / transforming growth factor beta receptor signaling pathway / cellular response to nerve growth factor stimulus / protein-DNA complex / response to gamma radiation / mitochondrion organization / nuclear estrogen receptor binding / Downregulation of SMAD2/3:SMAD4 transcriptional activity / DNA Damage Recognition in GG-NER / protein modification process / Dual Incision in GG-NER / histone deacetylase binding / cellular response to insulin stimulus / positive regulation of protein localization to nucleus / Formation of Incision Complex in GG-NER / cellular response to amyloid-beta / cellular response to UV / NAD binding / double-strand break repair / nuclear envelope / regulation of protein localization / 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 / damaged DNA binding / chromosome, telomeric region / nuclear body / innate immune response / DNA repair / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / ubiquitin protein ligase binding / chromatin / nucleolus / apoptotic process / protein kinase binding / negative regulation of transcription by RNA polymerase II / enzyme binding / 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-8E6 / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsLiu, Q. / Xu, Y.
CitationJournal: Eur J Med Chem / Year: 2018
Title: Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors
Authors: Chen, X. / Huan, X. / Liu, Q. / Wang, Y. / He, Q. / Tan, C. / Chen, Y. / Ding, J. / Xu, Y. / Miao, Z. / Yang, C.
History
DepositionJun 15, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 25, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 22, 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 1.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5673
Polymers39,1551
Non-polymers4122
Water84747
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint-17 kcal/mol
Surface area16200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.980, 93.980, 222.800
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522

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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: 39154.781 Da / Num. of mol.: 1 / Fragment: UNP residues 662-1011
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1, ADPRT, PPOL / Production host: Enterobacteria phage L1 (virus) / References: UniProt: P09874, NAD+ ADP-ribosyltransferase
#2: Chemical ChemComp-8E6 / 6-fluoranyl-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-1~{H}-benzimidazole-4-carboxamide


Mass: 316.353 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H13FN4OS
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 47 / 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: 3.63 Å3/Da / Density % sol: 66.09 %
Crystal growTemperature: 283 K / Method: vapor diffusion, hanging drop / Details: 80mM NaCl, 1.9M (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 22, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.3→39.709 Å / Num. obs: 48849 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 6.32 % / Biso Wilson estimate: 51.1 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.06 / Rrim(I) all: 0.065 / Χ2: 1.067 / Net I/σ(I): 17.95
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2.3-2.366.360.8022.2636090.7590.87699.9
2.36-2.426.3630.6232.9335180.8320.68100
2.42-2.496.3690.5243.534200.8860.572100
2.49-2.576.3710.4084.533400.9310.445100
2.57-2.666.3880.3535.2732230.9470.385100
2.66-2.756.3970.2726.7831240.9630.296100
2.75-2.856.3940.1849.7830480.9810.2100
2.85-2.976.3710.14212.0528680.990.155100
2.97-3.16.3710.10416.1527840.9940.113100
3.1-3.256.3610.07721.1926630.9970.084100
3.25-3.436.2830.05727.5925170.9980.062100
3.43-3.646.2590.0531.7423890.9980.054100
3.64-3.896.2050.04534.2722500.9980.049100
3.89-4.26.2020.04137.1420720.9980.045100
4.2-4.66.1560.03839.7419420.9990.042100
4.6-5.146.0750.03740.417380.9990.0499.8
5.14-5.946.2910.03539.0115360.9990.03899.9
5.94-7.276.4450.0340.7512980.9990.03399.9
7.27-10.296.310.02745.849880.9990.02999.2
10.29-39.7095.7240.02443.515220.9990.02694.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation5.35 Å46.99 Å
Translation5.35 Å46.99 Å

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASER2.7.16model building
PHENIX1.11.1_2575: ???refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HHY

4hhy


Resolution: 2.3→39.709 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 25.7
RfactorNum. reflection% reflection
Rfree0.2356 1463 3 %
Rwork0.202 --
obs0.203 48842 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 172.03 Å2 / Biso mean: 65.815 Å2 / Biso min: 29.52 Å2
Refinement stepCycle: final / Resolution: 2.3→39.709 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2648 0 27 47 2722
Biso mean--51.51 54.93 -
Num. residues----350
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082730
X-RAY DIFFRACTIONf_angle_d0.963705
X-RAY DIFFRACTIONf_chiral_restr0.058421
X-RAY DIFFRACTIONf_plane_restr0.006474
X-RAY DIFFRACTIONf_dihedral_angle_d7.322270
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3001-2.38230.32861460.271346914837100
2.3823-2.47760.30871500.252347854935100
2.4776-2.59040.27941470.254147214868100
2.5904-2.72690.32061450.262747354880100
2.7269-2.89770.29151450.252747494894100
2.8977-3.12140.25841440.246547544898100
3.1214-3.43530.2371400.221147354875100
3.4353-3.93210.25221440.18647604904100
3.9321-4.95250.17411490.151447484897100
4.9525-39.7150.21951530.18664701485499
Refinement TLS params.Method: refined / Origin x: 27.7607 Å / Origin y: -14.4397 Å / Origin z: -17.1141 Å
111213212223313233
T0.5293 Å20.0508 Å20.0357 Å2-0.2173 Å20.0143 Å2--0.3433 Å2
L1.6227 °2-0.8678 °2-0.217 °2-2.0829 °2-0.1261 °2--1.5111 °2
S0.0889 Å °0.0762 Å °0.0471 Å °0.0133 Å °-0.1069 Å °-0.2002 Å °-0.0474 Å °-0.0668 Å °0.0015 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA0 - 349
2X-RAY DIFFRACTION1allB1
3X-RAY DIFFRACTION1allC1
4X-RAY DIFFRACTION1allS1 - 79

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