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- PDB-5nwd: Crystal structure of TNKS2 in complex with 2-[4-(diethylamino)phe... -

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Basic information

Entry
Database: PDB / ID: 5nwd
TitleCrystal structure of TNKS2 in complex with 2-[4-(diethylamino)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 / NAD+ ADP-ribosyltransferase / protein localization to chromosome, telomeric region / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein poly-ADP-ribosylation / pericentriolar material / NAD+-protein ADP-ribosyltransferase activity / positive regulation of telomere capping / NAD+-protein poly-ADP-ribosyltransferase activity ...XAV939 stabilizes AXIN / NAD+ ADP-ribosyltransferase / protein localization to chromosome, telomeric region / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein poly-ADP-ribosylation / pericentriolar material / NAD+-protein ADP-ribosyltransferase activity / positive regulation of telomere capping / NAD+-protein poly-ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / 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 / cytosol / cytoplasm
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. ...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) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Special / Ankyrin repeat-containing domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
2-[4-(diethylamino)phenyl]-3~{H}-quinazolin-4-one / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 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)55,82913
Polymers54,6364
Non-polymers1,1949
Water5,891327
1
A: Tankyrase-2
H: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,9617
Polymers27,3182
Non-polymers6435
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6600 Å2
ΔGint-70 kcal/mol
Surface area10330 Å2
MethodPISA
2
B: Tankyrase-2
I: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,8696
Polymers27,3182
Non-polymers5514
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6430 Å2
ΔGint-68 kcal/mol
Surface area10310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.910, 98.430, 118.800
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-1331-

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, 336 molecules

#3: Chemical ChemComp-9C8 / 2-[4-(diethylamino)phenyl]-3~{H}-quinazolin-4-one


Mass: 293.363 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H19N3O
#4: Chemical ChemComp-ZN / ZINC ION


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


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#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.: 327 / 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: 2.43 Å3/Da / Density % sol: 49.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5 / 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: 1.45→44.38 Å / Num. obs: 93885 / % possible obs: 99.7 % / Redundancy: 5.2 % / Rmerge(I) obs: 0.044 / Net I/σ(I): 15.41

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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: 1.45→44.38 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.967 / SU B: 1.202 / SU ML: 0.045 / Cross valid method: THROUGHOUT / ESU R: 0.059 / ESU R Free: 0.059 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19184 4695 5 %RANDOM
Rwork0.17726 ---
obs0.17801 89189 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 24.148 Å2
Baniso -1Baniso -2Baniso -3
1--0.3 Å20 Å20 Å2
2---1.1 Å2-0 Å2
3---1.4 Å2
Refinement stepCycle: 1 / Resolution: 1.45→44.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3347 0 72 327 3746
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0193578
X-RAY DIFFRACTIONr_bond_other_d0.0030.023287
X-RAY DIFFRACTIONr_angle_refined_deg1.2951.9534831
X-RAY DIFFRACTIONr_angle_other_deg0.9263.0037552
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1195433
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.05922.903186
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.30615597
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4071530
X-RAY DIFFRACTIONr_chiral_restr0.0740.2479
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024111
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02933
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_it1.212.2271689
X-RAY DIFFRACTIONr_mcbond_other1.2072.2271689
X-RAY DIFFRACTIONr_mcangle_it1.9423.3322112
X-RAY DIFFRACTIONr_mcangle_other1.9433.3342113
X-RAY DIFFRACTIONr_scbond_it1.7392.4651889
X-RAY DIFFRACTIONr_scbond_other1.7392.4651889
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.7983.6162712
X-RAY DIFFRACTIONr_long_range_B_refined4.1626.1383998
X-RAY DIFFRACTIONr_long_range_B_other4.04725.7593942
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.45→1.488 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 345 -
Rwork0.314 6554 -
obs--99.83 %

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