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- PDB-4zzx: Structure of PARP2 catalytic domain bound to an isoindolinone inh... -

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Basic information

Entry
Database: PDB / ID: 4zzx
TitleStructure of PARP2 catalytic domain bound to an isoindolinone inhibitor
ComponentsPOLY [ADP-RIBOSE] POLYMERASE 2
KeywordsTRANSFERASE
Function / homology
Function and homology information


hippocampal neuron apoptotic process / response to oxygen-glucose deprivation / 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 / NAD+- protein-aspartate ADP-ribosyltransferase activity / NAD+-protein-glutamate ADP-ribosyltransferase activity / DNA ADP-ribosylation / HDR through MMEJ (alt-NHEJ) ...hippocampal neuron apoptotic process / response to oxygen-glucose deprivation / 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 / NAD+- protein-aspartate ADP-ribosyltransferase activity / NAD+-protein-glutamate ADP-ribosyltransferase activity / DNA ADP-ribosylation / HDR through MMEJ (alt-NHEJ) / poly-ADP-D-ribose modification-dependent protein binding / DNA repair-dependent chromatin remodeling / NAD+ ADP-ribosyltransferase / protein auto-ADP-ribosylation / protein poly-ADP-ribosylation / site of DNA damage / NAD+-protein ADP-ribosyltransferase activity / decidualization / NAD+ ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / nucleosome binding / POLB-Dependent Long Patch Base Excision Repair / extrinsic apoptotic signaling pathway / nucleotidyltransferase activity / DNA Damage Recognition in GG-NER / base-excision repair / 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
Similarity search - Function
Poly(ADP-ribose) polymerase, regulatory domain / Poly(ADP-ribose) Polymerase; domain 1 / WGR domain profile. / Poly(ADP-ribose) polymerase, regulatory domain / WGR domain / WGR domain superfamily / WGR domain / Proposed nucleic acid binding domain / Poly(ADP-ribose) polymerase, regulatory domain superfamily / Poly(ADP-ribose) polymerase, regulatory domain ...Poly(ADP-ribose) polymerase, regulatory domain / Poly(ADP-ribose) Polymerase; domain 1 / WGR domain profile. / Poly(ADP-ribose) polymerase, regulatory domain / WGR domain / WGR domain superfamily / WGR domain / 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-FSU / Poly [ADP-ribose] polymerase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 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 1.2Mar 6, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.3Jan 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
B: POLY [ADP-RIBOSE] POLYMERASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,7014
Polymers82,2052
Non-polymers4972
Water5,621312
1
A: POLY [ADP-RIBOSE] POLYMERASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,3512
Polymers41,1021
Non-polymers2481
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: POLY [ADP-RIBOSE] POLYMERASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,3512
Polymers41,1021
Non-polymers2481
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.460, 72.740, 141.340
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 2 / PARP-2 / HPARP-2 / ADP-RIBOSYLTRANSFERASE DIPHTHERIA TOXIN-LIKE 2 / ARTD2 / NAD(+) ADP- ...PARP-2 / HPARP-2 / ADP-RIBOSYLTRANSFERASE DIPHTHERIA TOXIN-LIKE 2 / ARTD2 / NAD(+) ADP-RIBOSYLTRANSFERASE 2 / ADPRT-2 / POLYADP-RIBOSE 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 POLYMERASE 2 / POLY ADP-RIBOSE POLYMERASE 2


Mass: 41102.309 Da / Num. of mol.: 2 / 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-FSU / 2-(3-methoxypropyl)-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide


Mass: 248.278 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H16N2O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 312 / Source method: isolated from a natural source / Formula: H2O

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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: 2.2 Å3/Da / Density % sol: 44.6 % / Description: NONE
Crystal growTemperature: 277 K
Details: 25% PEG4000, 0.2M MAGNESIUM CHLORIDE, 0.1 M TRIS PH 8.5, 277K

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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: 1.65→40 Å / Num. obs: 89473 / % possible obs: 99.6 % / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Rmerge(I) obs: 0.08
Reflection shellResolution: 1.65→1.74 Å / Mean I/σ(I) obs: 0.37 / % possible all: 99.5

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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: 1.65→30.67 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.928 / SU B: 2.04 / SU ML: 0.071 / Cross valid method: THROUGHOUT / ESU R: 0.112 / ESU R Free: 0.109 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2441 4478 5 %RANDOM
Rwork0.21274 ---
obs0.21434 84921 99.51 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.089 Å2
Baniso -1Baniso -2Baniso -3
1--0.31 Å20 Å20 Å2
2--0.12 Å20 Å2
3---0.19 Å2
Refinement stepCycle: LAST / Resolution: 1.65→30.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5576 0 36 312 5924
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.025736
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2981.987746
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5785698
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.13224.44259
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.942151045
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8391530
X-RAY DIFFRACTIONr_chiral_restr0.0840.2847
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214288
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: 1.654→1.697 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.32 293 -
Rwork0.275 5818 -
obs--99.01 %

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