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- PDB-5nt4: Crystal structure of TNKS2 in complex with 2-[4-(morpholin-4-yl)p... -

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Basic information

Entry
Database: PDB / ID: 5nt4
TitleCrystal structure of TNKS2 in complex with 2-[4-(morpholin-4-yl)phenyl]-3,4-dihydroquinazolin-4-one
Components(Tankyrase-2) x 2
KeywordsHYDROLASE / Tankyrase / Inhibitor / ARTD6 / PARP5b
Function / homology
Function and homology information


XAV939 stabilizes AXIN / NAD+ ADP-ribosyltransferase / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein localization to chromosome, telomeric region / protein poly-ADP-ribosylation / pericentriolar material / NAD+-protein ADP-ribosyltransferase activity / positive regulation of telomere capping / Transferases; Glycosyltransferases; Pentosyltransferases ...XAV939 stabilizes AXIN / NAD+ ADP-ribosyltransferase / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein localization to chromosome, telomeric region / protein poly-ADP-ribosylation / pericentriolar material / NAD+-protein ADP-ribosyltransferase activity / positive regulation of telomere capping / Transferases; Glycosyltransferases; Pentosyltransferases / NAD+-protein poly-ADP-ribosyltransferase activity / positive regulation of telomere maintenance via telomerase / nucleotidyltransferase activity / TCF dependent signaling in response to WNT / Degradation of AXIN / Wnt signaling pathway / Regulation of PTEN stability and activity / protein polyubiquitination / positive regulation of canonical Wnt signaling pathway / nuclear envelope / chromosome, telomeric region / Ub-specific processing proteases / Golgi membrane / perinuclear region of cytoplasm / enzyme binding / nucleus / metal ion binding / cytoplasm / cytosol
Similarity search - Function
YefM-like fold / YefM-like fold - #10 / Ankyrin repeat / Phosphoenolpyruvate Carboxykinase; domain 3 - #10 / Other non-globular / Phosphoenolpyruvate Carboxykinase; domain 3 / Ankyrin repeats (many copies) / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. ...YefM-like fold / YefM-like fold - #10 / Ankyrin repeat / Phosphoenolpyruvate Carboxykinase; domain 3 - #10 / Other non-globular / Phosphoenolpyruvate Carboxykinase; domain 3 / Ankyrin repeats (many copies) / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Special / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
2-[4-morpholin-4-yl]-3,4-dihydroquinazolin-4-one / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsNkizinkiko, Y. / Haikarainen, T. / Lehtio, L.
Funding support Finland, 1items
OrganizationGrant numberCountry
Biocenter Oulu Finland
CitationJournal: Sci Rep / Year: 2018
Title: 2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors.
Authors: Nkizinkiko, Y. / Desantis, J. / Koivunen, J. / Haikarainen, T. / Murthy, S. / Sancineto, L. / Massari, S. / Ianni, F. / Obaji, E. / Loza, M.I. / Pihlajaniemi, T. / Brea, J. / Tabarrini, O. / Lehtio, L.
History
DepositionApr 27, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 7, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 3, 2018Group: Data collection / Category: diffrn_source
Item: _diffrn_source.pdbx_synchrotron_beamline / _diffrn_source.type
Revision 1.2Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.3Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tankyrase-2
H: Tankyrase-2
B: Tankyrase-2
I: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,85713
Polymers54,6364
Non-polymers1,2229
Water4,234235
1
A: Tankyrase-2
H: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,9757
Polymers27,3182
Non-polymers6575
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6600 Å2
ΔGint-69 kcal/mol
Surface area10340 Å2
MethodPISA
2
B: Tankyrase-2
I: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,8836
Polymers27,3182
Non-polymers5654
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6470 Å2
ΔGint-68 kcal/mol
Surface area10320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.060, 98.150, 118.380
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11B-1345-

HOH

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABHI

#1: Protein Tankyrase-2 / TANK2 / ADP-ribosyltransferase diphtheria toxin-like 6 / ARTD6 / Poly [ADP-ribose] polymerase 5B / ...TANK2 / ADP-ribosyltransferase diphtheria toxin-like 6 / ARTD6 / Poly [ADP-ribose] polymerase 5B / TNKS-2 / TRF1-interacting ankyrin-related ADP-ribose polymerase 2 / Tankyrase II / Tankyrase-like protein / Tankyrase-related protein


Mass: 21824.545 Da / Num. of mol.: 2 / Fragment: UNP residues 946-1113
Source method: isolated from a genetically manipulated source
Details: Biomolecule / Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Plasmid: PNIC-BS4A / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta2 / References: UniProt: Q9H2K2, NAD+ ADP-ribosyltransferase
#2: Protein/peptide Tankyrase-2 / TANK2 / ADP-ribosyltransferase diphtheria toxin-like 6 / ARTD6 / Poly [ADP-ribose] polymerase 5B / ...TANK2 / ADP-ribosyltransferase diphtheria toxin-like 6 / ARTD6 / Poly [ADP-ribose] polymerase 5B / TNKS-2 / TRF1-interacting ankyrin-related ADP-ribose polymerase 2 / Tankyrase II / Tankyrase-like protein / Tankyrase-related protein


Mass: 5493.216 Da / Num. of mol.: 2 / Fragment: UNP residues 1114-1162
Source method: isolated from a genetically manipulated source
Details: Biomolecule / Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Plasmid: PNIC-BS4A / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta2 / References: UniProt: Q9H2K2, NAD+ ADP-ribosyltransferase

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Non-polymers , 5 types, 244 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-97Z / 2-[4-morpholin-4-yl]-3,4-dihydroquinazolin-4-one


Mass: 307.346 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17N3O2
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.39 Å3/Da / Density % sol: 48.64 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 0.2 M LISO4, 0.1 M TRIS HCL, 24% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.965 Å
DetectorType: DECTRIS PILATUS3 R CdTe 300K / Detector: PIXEL / Date: Nov 20, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.965 Å / Relative weight: 1
ReflectionResolution: 1.9→49.08 Å / Num. obs: 41600 / % possible obs: 100 % / Redundancy: 6.69 % / Rmerge(I) obs: 0.116 / Net I/σ(I): 11.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3U9H

3u9h


Resolution: 1.9→49.08 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.952 / SU B: 3.16 / SU ML: 0.089 / Cross valid method: THROUGHOUT / ESU R: 0.129 / ESU R Free: 0.121 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20412 2080 5 %RANDOM
Rwork0.17324 ---
obs0.17479 39520 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 31.597 Å2
Baniso -1Baniso -2Baniso -3
1--0.24 Å2-0 Å20 Å2
2---1.68 Å2-0 Å2
3---1.92 Å2
Refinement stepCycle: 1 / Resolution: 1.9→49.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3347 0 74 235 3656
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0193545
X-RAY DIFFRACTIONr_bond_other_d0.0020.023245
X-RAY DIFFRACTIONr_angle_refined_deg1.521.9524783
X-RAY DIFFRACTIONr_angle_other_deg1.0373.0047453
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3685425
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.27722.935184
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.99215584
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8941529
X-RAY DIFFRACTIONr_chiral_restr0.0880.2474
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.024069
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02926
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_it2.252.9061679
X-RAY DIFFRACTIONr_mcbond_other2.252.9041678
X-RAY DIFFRACTIONr_mcangle_it3.2944.3312096
X-RAY DIFFRACTIONr_mcangle_other3.2934.3332097
X-RAY DIFFRACTIONr_scbond_it2.8343.2751865
X-RAY DIFFRACTIONr_scbond_other2.8333.2751865
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.634.772682
X-RAY DIFFRACTIONr_long_range_B_refined6.42733.713991
X-RAY DIFFRACTIONr_long_range_B_other6.42633.7063992
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.374 151 -
Rwork0.353 2868 -
obs--99.9 %

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