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- PDB-5wrq: Structure of human PARP1 catalytic domain bound to a quinazoline-... -

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Basic information

Entry
Database: PDB / ID: 5wrq
TitleStructure of human PARP1 catalytic domain bound to a quinazoline-2,4(1H,3H)-dione inhibitor
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 / 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) / 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 / negative regulation of cGAS/STING signaling pathway / 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 / POLB-Dependent Long Patch Base Excision Repair / nucleosome binding / positive regulation of double-strand break repair via homologous recombination / 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 / protein-DNA complex / mitochondrion organization / nuclear estrogen receptor binding / 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 / histone deacetylase binding / positive regulation of protein localization to nucleus / Formation of Incision Complex in GG-NER / cellular response to insulin stimulus / 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 / ubiquitin protein ligase binding / DNA damage response / chromatin binding / chromatin / nucleolus / protein kinase binding / apoptotic process / 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-7TX / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.65 Å
AuthorsCao, R. / Wang, Y.L. / Zhou, J. / Huang, N. / Xu, B.L.
CitationJournal: To Be Published
Title: Structure of human PARP1 catalytic domain bound to a quinazoline-2,4(1H,3H)-dione inhibitor
Authors: Cao, R. / Wang, Y.L. / Zhou, J. / Huang, N. / Xu, B.L.
History
DepositionDec 3, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 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

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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)79,7814
Polymers78,8762
Non-polymers9052
Water00
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8912
Polymers39,4381
Non-polymers4531
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8912
Polymers39,4381
Non-polymers4531
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.340, 92.360, 163.440
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 39438.148 Da / Num. of mol.: 2 / Fragment: catalytic domain, UNP residues 662-1011 / Mutation: V762A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1 / Production host: Escherichia coli (E. coli) / References: UniProt: P09874, NAD+ ADP-ribosyltransferase
#2: Chemical ChemComp-7TX / 5-[[2,4-bis(oxidanylidene)quinazolin-1-yl]methyl]-2-fluoranyl-N-[(3R)-1-(3-methylbutyl)pyrrolidin-3-yl]benzamide


Mass: 452.521 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H29FN4O3

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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: 2.31 Å3/Da / Density % sol: 46.82 %
Description: The entry contains Friedel pairs in F_Plus/Minus columns
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 2.5M AMMONIUM SULFATE, 100mM TRIS

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 5, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.03→92.31 Å / Num. obs: 24427 / % possible obs: 99.9 % / Redundancy: 11.9 % / Net I/σ(I): 17.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0123refinement
iMOSFLMdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementResolution: 2.65→81.72 Å / Cor.coef. Fo:Fc: 0.894 / Cor.coef. Fo:Fc free: 0.854 / SU B: 15.453 / SU ML: 0.321 / Cross valid method: THROUGHOUT / ESU R Free: 0.415
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. The entry contains Friedel pairs in F_Plus/Minus columns
RfactorNum. reflection% reflectionSelection details
Rfree0.29741 1054 4.8 %RANDOM
Rwork0.25347 ---
obs0.25555 20950 99.79 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 41.706 Å2
Baniso -1Baniso -2Baniso -3
1-1 Å20 Å20 Å2
2--2.22 Å2-0 Å2
3----3.22 Å2
Refinement stepCycle: 1 / Resolution: 2.65→81.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5526 0 66 0 5592
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0195722
X-RAY DIFFRACTIONr_bond_other_d0.0030.025590
X-RAY DIFFRACTIONr_angle_refined_deg1.21.9937726
X-RAY DIFFRACTIONr_angle_other_deg1.0473.00512934
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7015698
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.13625.203246
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.859151062
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.6961522
X-RAY DIFFRACTIONr_chiral_restr0.0670.2862
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0216346
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021220
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3244.1952804
X-RAY DIFFRACTIONr_mcbond_other1.3244.1932803
X-RAY DIFFRACTIONr_mcangle_it2.486.283498
X-RAY DIFFRACTIONr_mcangle_other2.486.2813499
X-RAY DIFFRACTIONr_scbond_it0.6984.2122918
X-RAY DIFFRACTIONr_scbond_other0.6984.2122919
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.4386.2734229
X-RAY DIFFRACTIONr_long_range_B_refined4.24131.7646095
X-RAY DIFFRACTIONr_long_range_B_other4.24131.7676096
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.65→2.719 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.405 84 -
Rwork0.314 1513 -
obs--99.75 %

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