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- PDB-5nwg: Crystal structure of TNKS2 in complex with 7-chloro-2-{4-[(2-hydr... -

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Basic information

Entry
Database: PDB / ID: 5nwg
TitleCrystal structure of TNKS2 in complex with 7-chloro-2-{4-[(2-hydroxyethyl)(methyl)amino]phenyl}-3,4-dihydroquinazolin-4-one
Components(Tankyrase-2) x 2
KeywordsTRANSFERASE / Tankyrase / Inhibitor / ARTD6 / PARP5b / ADP-ribosyltransferase
Function / homology
Function and homology information


XAV939 stabilizes AXIN / positive regulation of telomere capping / NAD+ ADP-ribosyltransferase / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein localization to chromosome, telomeric region / NAD+-protein-aspartate ADP-ribosyltransferase activity / protein poly-ADP-ribosylation / NAD+-protein-glutamate ADP-ribosyltransferase activity / NAD+-protein mono-ADP-ribosyltransferase activity ...XAV939 stabilizes AXIN / positive regulation of telomere capping / NAD+ ADP-ribosyltransferase / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein localization to chromosome, telomeric region / NAD+-protein-aspartate ADP-ribosyltransferase activity / protein poly-ADP-ribosylation / NAD+-protein-glutamate ADP-ribosyltransferase activity / NAD+-protein mono-ADP-ribosyltransferase activity / pericentriolar material / Transferases; Glycosyltransferases; Pentosyltransferases / NAD+ 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 / metal ion binding / nucleus / 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 / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. / SAM domain (Sterile alpha motif) ...YefM-like fold / YefM-like fold - #10 / Ankyrin repeat / Phosphoenolpyruvate Carboxykinase; domain 3 - #10 / Other non-globular / Phosphoenolpyruvate Carboxykinase; domain 3 / 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) / Special / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-9CB / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 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
DepositionMay 5, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 14, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.2Jan 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)55,80612
Polymers54,6364
Non-polymers1,1718
Water8,215456
1
A: Tankyrase-2
H: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,9016
Polymers27,3182
Non-polymers5834
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6290 Å2
ΔGint-49 kcal/mol
Surface area10440 Å2
MethodPISA
2
B: Tankyrase-2
I: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,9056
Polymers27,3182
Non-polymers5874
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6580 Å2
ΔGint-69 kcal/mol
Surface area10290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.690, 98.410, 119.930
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
11A-1387-

HOH

21B-1368-

HOH

31I-1233-

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
Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Plasmid: PNIC-BSA4 / 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
Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Plasmid: PNIC-BSA4 / 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, 464 molecules

#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-9CB / 7-chloranyl-2-[4-[2-hydroxyethyl(methyl)amino]phenyl]-3~{H}-quinazolin-4-one


Mass: 329.781 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H16ClN3O2
#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.: 456 / 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: 2.45 Å3/Da / Density % sol: 49.81 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.2 M LISO4, 0.1 M TRIS HCL, 24/26 % PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.953723 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 10, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.953723 Å / Relative weight: 1
ReflectionResolution: 1.4→45.52 Å / Num. obs: 104195 / % possible obs: 99 % / Redundancy: 3.8 % / Rmerge(I) obs: 0.091 / Net I/σ(I): 11.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3U9H

3u9h


Resolution: 1.4→45.52 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.97 / SU B: 1.913 / SU ML: 0.033 / Cross valid method: THROUGHOUT / ESU R: 0.052 / ESU R Free: 0.049 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.16905 5210 5 %RANDOM
Rwork0.14134 ---
obs0.1427 98985 98.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 20.718 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å2-0 Å2-0 Å2
2--0.09 Å20 Å2
3----0.13 Å2
Refinement stepCycle: 1 / Resolution: 1.4→45.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3342 0 69 456 3867
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0193810
X-RAY DIFFRACTIONr_bond_other_d0.0030.023376
X-RAY DIFFRACTIONr_angle_refined_deg1.3881.9725184
X-RAY DIFFRACTIONr_angle_other_deg0.9813.0047873
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9645481
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.17223.061196
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.48715650
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2741531
X-RAY DIFFRACTIONr_chiral_restr0.0840.2510
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214335
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02860
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_it1.761.8311752
X-RAY DIFFRACTIONr_mcbond_other1.7561.8291751
X-RAY DIFFRACTIONr_mcangle_it2.2642.7522205
X-RAY DIFFRACTIONr_mcangle_other2.2642.7542206
X-RAY DIFFRACTIONr_scbond_it1.8432.1242058
X-RAY DIFFRACTIONr_scbond_other1.8432.1242058
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.3053.0782950
X-RAY DIFFRACTIONr_long_range_B_refined3.48422.2934436
X-RAY DIFFRACTIONr_long_range_B_other3.48422.2894437
X-RAY DIFFRACTIONr_rigid_bond_restr1.72637186
X-RAY DIFFRACTIONr_sphericity_free25.5235286
X-RAY DIFFRACTIONr_sphericity_bonded9.16657237
LS refinement shellResolution: 1.4→1.436 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 375 -
Rwork0.271 7126 -
obs--97.49 %

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