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- PDB-8he8: Human ADP-ribosyltransferase 2 (PARP2) catalytic domain bound to ... -

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Basic information

Entry
Database: PDB / ID: 8he8
TitleHuman ADP-ribosyltransferase 2 (PARP2) catalytic domain bound to a quinazoline-2,4(1H,3H)-dione inhibitor
ComponentsPoly [ADP-ribose] polymerase 2
KeywordsTRANSFERASE / PARP-2 / DNA ADP-ribosyltransferase / Inhibitor
Function / homology
Function and homology information


response to oxygen-glucose deprivation / hippocampal neuron apoptotic process / poly-ADP-D-ribose binding / positive regulation of cell growth involved in cardiac muscle cell development / NAD+-protein-serine ADP-ribosyltransferase activity / NAD DNA ADP-ribosyltransferase activity / DNA ADP-ribosylation / poly-ADP-D-ribose modification-dependent protein binding / HDR through MMEJ (alt-NHEJ) / NAD+ ADP-ribosyltransferase ...response to oxygen-glucose deprivation / hippocampal neuron apoptotic process / poly-ADP-D-ribose binding / positive regulation of cell growth involved in cardiac muscle cell development / NAD+-protein-serine ADP-ribosyltransferase activity / NAD DNA ADP-ribosyltransferase activity / DNA ADP-ribosylation / poly-ADP-D-ribose modification-dependent protein binding / HDR through MMEJ (alt-NHEJ) / NAD+ ADP-ribosyltransferase / protein auto-ADP-ribosylation / NAD+-protein-aspartate ADP-ribosyltransferase activity / protein poly-ADP-ribosylation / NAD+-protein-glutamate ADP-ribosyltransferase activity / DNA repair-dependent chromatin remodeling / NAD+-protein mono-ADP-ribosyltransferase activity / decidualization / site of DNA damage / Transferases; Glycosyltransferases; Pentosyltransferases / POLB-Dependent Long Patch Base Excision Repair / NAD+ poly-ADP-ribosyltransferase activity / nucleosome binding / extrinsic apoptotic signaling pathway / nucleotidyltransferase activity / base-excision repair / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / Formation of Incision Complex in GG-NER / double-strand break repair / damaged DNA binding / DNA repair / DNA damage response / chromatin binding / nucleolus / nucleoplasm / nucleus / cytosol
Similarity search - Function
: / 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. ...: / 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. / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile.
Similarity search - Domain/homology
Chem-1WI / Poly [ADP-ribose] polymerase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.05 Å
AuthorsWang, X.Y. / Xu, B.L. / Zhou, J.
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

Downloads & links

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Assembly

Deposited unit
A: Poly [ADP-ribose] polymerase 2
B: Poly [ADP-ribose] polymerase 2
C: Poly [ADP-ribose] polymerase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,0198
Polymers119,4353
Non-polymers1,5845
Water34219
1
A: Poly [ADP-ribose] polymerase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,3703
Polymers39,8121
Non-polymers5592
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,3703
Polymers39,8121
Non-polymers5592
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Poly [ADP-ribose] polymerase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,2782
Polymers39,8121
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.113, 103.362, 134.925
Angle α, β, γ (deg.)90.000, 92.040, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Poly [ADP-ribose] polymerase 2 / PARP-2 / hPARP-2 / ADP-ribosyltransferase diphtheria toxin-like 2 / ARTD2 / DNA ADP- ...PARP-2 / hPARP-2 / ADP-ribosyltransferase diphtheria toxin-like 2 / ARTD2 / DNA ADP-ribosyltransferase PARP2 / NAD(+) ADP-ribosyltransferase 2 / ADPRT-2 / Poly[ADP-ribose] synthase 2 / pADPRT-2 / Protein poly-ADP-ribosyltransferase PARP2


Mass: 39811.742 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP2, ADPRT2, ADPRTL2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9UGN5, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#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-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.: 3 / Source method: obtained synthetically / Formula: C25H27FN4O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 19 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.4 Å3/Da / Density % sol: 48.72 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 25% PEG-3350, 0.1 M Tris-HCl pH 8.3-8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 14, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 3.05→48.26 Å / Num. obs: 19445 / % possible obs: 90 % / Redundancy: 4.7 % / Biso Wilson estimate: 56.6 Å2 / CC1/2: 0.989 / Rmerge(I) obs: 0.146 / Rpim(I) all: 0.071 / Rrim(I) all: 0.164 / Net I/σ(I): 10.18
Reflection shellResolution: 3.05→3.159 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.5886 / Mean I/σ(I) obs: 2.46 / Num. unique obs: 2013 / CC1/2: 0.785 / Rpim(I) all: 0.2847 / Rrim(I) all: 0.6574 / % possible all: 92.04

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Processing

Software
NameVersionClassification
autoPROCdata processing
MOLREPphasing
PHENIX1.20.1_4487refinement
REFMACv8refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4TVJ

4tvj


Resolution: 3.05→41.09 Å / SU ML: 0.3284 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 25.7854
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2563 924 4.76 %
Rwork0.2074 18491 -
obs0.2098 19415 89.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 55.66 Å2
Refinement stepCycle: LAST / Resolution: 3.05→41.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8344 0 114 19 8477
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00318639
X-RAY DIFFRACTIONf_angle_d0.673111663
X-RAY DIFFRACTIONf_chiral_restr0.0391259
X-RAY DIFFRACTIONf_plane_restr0.00451498
X-RAY DIFFRACTIONf_dihedral_angle_d11.23051177
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.05-3.210.29951430.25562686X-RAY DIFFRACTION91.73
3.21-3.410.30381370.24182691X-RAY DIFFRACTION91.55
3.41-3.670.26791020.22212679X-RAY DIFFRACTION90.85
3.67-4.040.26621520.20752627X-RAY DIFFRACTION90.4
4.04-4.630.23251310.1952639X-RAY DIFFRACTION89.33
4.63-5.830.23511360.19792588X-RAY DIFFRACTION87.79
5.83-41.090.24051230.18562581X-RAY DIFFRACTION86.22

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