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- PDB-8he7: ADP-ribosyltransferase 1 (PARP1) catalytic domain bound to a quin... -

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Basic information

Entry
Database: PDB / ID: 8he7
TitleADP-ribosyltransferase 1 (PARP1) catalytic domain bound to a quinazoline-2,4(1H,3H)-dione inhibitor
ComponentsPoly [ADP-ribose] polymerase 1, processed C-terminus
KeywordsTRANSFERASE / DNA ADP-ribosyltransferase 1 / PARP1 / Inhibitor
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 / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / regulation of base-excision repair / 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 / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / regulation of base-excision repair / 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 / negative regulation of adipose tissue development / NAD DNA ADP-ribosyltransferase activity / DNA ADP-ribosylation / mitochondrial DNA metabolic process / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / replication fork reversal / ATP generation from poly-ADP-D-ribose / positive regulation of necroptotic process / transcription regulator activator activity / response to aldosterone / HDR through MMEJ (alt-NHEJ) / positive regulation of DNA-templated transcription, elongation / NAD+ ADP-ribosyltransferase / signal transduction involved in regulation of gene expression / protein auto-ADP-ribosylation / negative regulation of telomere maintenance via telomere lengthening / mitochondrial DNA repair / NAD+-protein-aspartate ADP-ribosyltransferase activity / protein poly-ADP-ribosylation / positive regulation of intracellular estrogen receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / NAD+-protein-glutamate ADP-ribosyltransferase activity / positive regulation of cardiac muscle hypertrophy / positive regulation of mitochondrial depolarization / cellular response to zinc ion / NAD+-protein mono-ADP-ribosyltransferase activity / nuclear replication fork / decidualization / protein autoprocessing / R-SMAD binding / macrophage differentiation / site of DNA damage / Transferases; Glycosyltransferases; Pentosyltransferases / negative regulation of transcription elongation by RNA polymerase II / POLB-Dependent Long Patch Base Excision Repair / positive regulation of SMAD protein signal transduction / NAD+ poly-ADP-ribosyltransferase activity / SUMOylation of DNA damage response and repair proteins / positive regulation of double-strand break repair via homologous recombination / nucleosome binding / protein localization to chromatin / nucleotidyltransferase activity / telomere maintenance / transforming growth factor beta receptor signaling pathway / negative regulation of innate immune response / nuclear estrogen receptor binding / response to gamma radiation / mitochondrion organization / Downregulation of SMAD2/3:SMAD4 transcriptional activity / enzyme activator activity / protein-DNA complex / cellular response to nerve growth factor stimulus / DNA Damage Recognition in GG-NER / protein modification process / Dual Incision in GG-NER / positive regulation of protein localization to nucleus / histone deacetylase binding / Formation of Incision Complex in GG-NER / cellular response to insulin stimulus / cellular response to amyloid-beta / NAD binding / cellular response to UV / nuclear envelope / double-strand break repair / regulation of protein localization / site of double-strand break / cellular response to oxidative stress / transcription regulator complex / damaged DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / transcription by RNA polymerase II / chromosome, telomeric region / positive regulation of canonical NF-kappaB signal transduction / nuclear body / innate immune response / DNA repair / negative regulation of DNA-templated transcription / apoptotic process / DNA damage response / ubiquitin protein ligase binding / chromatin binding / protein kinase binding / chromatin / nucleolus / enzyme binding / negative regulation of transcription by RNA polymerase II / 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. / 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
Chem-1WI / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsWang, X.Y. / Zhou, J. / Xu, B.L.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81673300 China
National Natural Science Foundation of China (NSFC)82173693 China
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of Quinazoline-2,4(1 H ,3 H )-dione Derivatives Containing a Piperizinone Moiety as Potent PARP-1/2 Inhibitors─Design, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis.
Authors: Zhou, J. / Du, T. / Wang, X. / Yao, H. / Deng, J. / Li, Y. / Chen, X. / Sheng, L. / Ji, M. / Xu, B.
History
DepositionNov 7, 2022Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Poly [ADP-ribose] polymerase 1, processed C-terminus
B: Poly [ADP-ribose] polymerase 1, processed C-terminus
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,7519
Polymers78,3382
Non-polymers1,4137
Water5,639313
1
A: Poly [ADP-ribose] polymerase 1, processed C-terminus
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8274
Polymers39,1691
Non-polymers6593
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint-16 kcal/mol
Surface area16510 Å2
MethodPISA
2
B: Poly [ADP-ribose] polymerase 1, processed C-terminus
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9245
Polymers39,1691
Non-polymers7554
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint-16 kcal/mol
Surface area16540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.428, 92.007, 162.805
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Poly [ADP-ribose] polymerase 1, processed C-terminus / Poly [ADP-ribose] polymerase 1 / 89-kDa form


Mass: 39168.809 Da / Num. of mol.: 2
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
#2: Chemical ChemComp-1WI / 1-[[4-fluoranyl-3-(3-oxidanylidene-4-pentan-3-yl-piperazin-1-yl)carbonyl-phenyl]methyl]quinazoline-2,4-dione


Mass: 466.505 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H27FN4O4
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 313 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.32 Å3/Da / Density % sol: 46.87 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 2.5 M (NH4)2SO4, 100 mM Tris-HCl, pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.979183 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 20, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979183 Å / Relative weight: 1
ReflectionResolution: 2.09→46.42 Å / Num. obs: 41898 / % possible obs: 95.9 % / Redundancy: 5.7 % / Biso Wilson estimate: 25.94 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.155 / Rpim(I) all: 0.07 / Rrim(I) all: 0.171 / Net I/σ(I): 6
Reflection shellResolution: 2.1→2.175 Å / Rmerge(I) obs: 0.1415 / Mean I/σ(I) obs: 11.17 / Num. unique obs: 41506 / CC1/2: 0.996 / Rpim(I) all: 0.06415 / Rrim(I) all: 0.1559

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Processing

Software
NameVersionClassification
autoPROCdata processing
MOLREPphasing
PHENIX1.20.1_4487refinement
REFMACv8refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7cmw

7cmw


Resolution: 2.1→46.42 Å / SU ML: 0.238 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.0803
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2502 2003 4.86 %
Rwork0.1903 39235 -
obs0.1933 41238 95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.81 Å2
Refinement stepCycle: LAST / Resolution: 2.1→46.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5504 0 93 313 5910
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00215702
X-RAY DIFFRACTIONf_angle_d0.54617706
X-RAY DIFFRACTIONf_chiral_restr0.0405850
X-RAY DIFFRACTIONf_plane_restr0.0032980
X-RAY DIFFRACTIONf_dihedral_angle_d5.9436776
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.150.33211370.23452683X-RAY DIFFRACTION93.22
2.15-2.210.30591210.21962852X-RAY DIFFRACTION96.65
2.21-2.280.29791240.21662378X-RAY DIFFRACTION82.74
2.28-2.350.24421210.21382945X-RAY DIFFRACTION99.93
2.35-2.430.32121450.20762916X-RAY DIFFRACTION99.71
2.43-2.530.28081810.20382884X-RAY DIFFRACTION99.8
2.53-2.650.26661500.21052877X-RAY DIFFRACTION99.51
2.65-2.780.29371390.20962662X-RAY DIFFRACTION90.65
2.78-2.960.26351570.19892894X-RAY DIFFRACTION98.9
2.96-3.190.2441480.1962917X-RAY DIFFRACTION98.93
3.19-3.510.2271370.18972534X-RAY DIFFRACTION85.72
3.51-4.020.2361410.16922566X-RAY DIFFRACTION86.02
4.02-5.060.21681330.15222998X-RAY DIFFRACTION99.27
5.06-46.420.21511690.18983129X-RAY DIFFRACTION98.8

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