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- PDB-4zzy: Structure of human PARP2 catalytic domain bound to an isoindolino... -

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Basic information

Entry
Database: PDB / ID: 4zzy
TitleStructure of human PARP2 catalytic domain bound to an isoindolinone inhibitor
ComponentsPOLY [ADP-RIBOSE] POLYMERASE 2
KeywordsTRANSFERASE
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 / NAD+ poly-ADP-ribosyltransferase activity / POLB-Dependent Long Patch Base Excision Repair / 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 / Poly(ADP-ribose) Polymerase; domain 1 / : / 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 / Poly(ADP-ribose) Polymerase; domain 1 / : / 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 / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. / Alpha-Beta Complex / Up-down Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-D7N / Poly [ADP-ribose] polymerase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsCasale, E. / Fasolini, M. / Papeo, G. / Posteri, H. / Borghi, D. / Busel, A.A. / Caprera, F. / Ciomei, M. / Cirla, A. / Corti, E. ...Casale, E. / Fasolini, M. / Papeo, G. / Posteri, H. / Borghi, D. / Busel, A.A. / Caprera, F. / Ciomei, M. / Cirla, A. / Corti, E. / DAnello, M. / Fasolini, M. / Felder, E.R. / Forte, B. / Galvani, A. / Isacchi, A. / Khvat, A. / Krasavin, M.Y. / Lupi, R. / Orsini, P. / Perego, R. / Pesenti, E. / Pezzetta, D. / Rainoldi, S. / RiccardiSirtori, F. / Scolaro, A. / Sola, F. / Zuccotto, F. / Donati, D. / Montagnoli, A.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of 2-[1-(4,4-Difluorocyclohexyl)Piperidin-4-Yl]-6-Fluoro-3-Oxo-2,3-Dihydro-1H-Isoindole-4-Carboxamide (Nms-P118): A Potent, Orally Available and Highly Selective Parp- 1 Inhibitor for Cancer Therapy.
Authors: Papeo, G.M.E. / Posteri, H. / Borghi, D. / Busel, A.A. / Caprera, F. / Casale, E. / Ciomei, M. / Cirla, A. / Corti, E. / D'Anello, M. / Fasolini, M. / Forte, B. / Galvani, A. / Isacchi, A. / ...Authors: Papeo, G.M.E. / Posteri, H. / Borghi, D. / Busel, A.A. / Caprera, F. / Casale, E. / Ciomei, M. / Cirla, A. / Corti, E. / D'Anello, M. / Fasolini, M. / Forte, B. / Galvani, A. / Isacchi, A. / Khvat, A. / Krasavin, M.Y. / Lupi, R. / Orsini, P. / Perego, R. / Pesenti, E. / Pezzetta, D. / Rainoldi, S. / Riccardi-Sirtori, F. / Scolaro, A. / Sola, F. / Zuccotto, F. / Felder, E.R. / Donati, D. / Montagnoli, A.
History
DepositionApr 15, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 23, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,4982
Polymers41,1021
Non-polymers3951
Water1,44180
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.377, 74.377, 148.463
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein POLY [ADP-RIBOSE] POLYMERASE 2 / PARP-2 / HPARP-2 / ADP-RIBOSYLTRANSFERASE DIPHTHERIA TOXIN-LI KE 2 / ARTD2 / NAD(+) ADP- ...PARP-2 / HPARP-2 / ADP-RIBOSYLTRANSFERASE DIPHTHERIA TOXIN-LI KE 2 / ARTD2 / NAD(+) ADP-RIBOSYLTRANSFERASE 2 / ADPRT-2 / POLYADP-RIB OSE SYNTHASE 2 / PADPRT-2 / PARP-2 / HPARP-2 / ADP-RIBOSYLTRANSFERASE DIPHTHERIA TOXIN-LIKE 2 / ARTD2 / NAD(+) ADP-RIBOSYLTRANSFERASE 2 / A DPRT-2 / POLYADP- RIBOSE SYNTHASE 2 / PADPRT-2 / POLY ADP-RIBOSE POLY MERASE 2 / POLY ADP-RIBOSE POLYMERASE 2


Mass: 41102.309 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, UNP RESIDUES 223-583
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET28A / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / References: UniProt: Q9UGN5, NAD+ ADP-ribosyltransferase
#2: Chemical ChemComp-D7N / 2-[1-(4,4-Difluorocyclohexyl)-piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide


Mass: 395.419 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H24F3N3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsGLY221 AND PRO222 ARE EXPRESSION TAG

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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: 2.54 Å3/Da / Density % sol: 51.2 % / Description: NONE
Crystal growDetails: 25% PEG4000, 0.2M MAGNESIUM CLORIDE, 0.1 M TRIS PH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.07
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. obs: 21921 / % possible obs: 99.8 % / Observed criterion σ(I): 0 / Redundancy: 7 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 20.6
Reflection shellResolution: 2.2→2.32 Å / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 6.5 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3KCZ

3kcz


Resolution: 2.2→66.5 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.883 / SU B: 7.135 / SU ML: 0.179 / Cross valid method: THROUGHOUT / ESU R: 0.273 / ESU R Free: 0.235 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.28037 1122 5.1 %RANDOM
Rwork0.21618 ---
obs0.21945 20733 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.354 Å2
Baniso -1Baniso -2Baniso -3
1--1.04 Å20 Å20 Å2
2---1.04 Å20 Å2
3---2.09 Å2
Refinement stepCycle: LAST / Resolution: 2.2→66.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2796 0 28 80 2904
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.022886
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8561.9883901
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7675349
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.84724.462130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.13815524
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7571515
X-RAY DIFFRACTIONr_chiral_restr0.1150.2427
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212152
X-RAY DIFFRACTIONr_gen_planes_other
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.396 83 -
Rwork0.308 1334 -
obs--99.86 %

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