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- PDB-8s60: Tankyrase 2 in complex with a quinazolin-4-one inhibitor -

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Basic information

Entry
Database: PDB / ID: 8s60
TitleTankyrase 2 in complex with a quinazolin-4-one inhibitor
Components(Poly [ADP-ribose] polymerase tankyrase- ...) x 2
KeywordsTRANSFERASE / Inhibitor / quinazolin-4-one / Tankyrase 2
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 / pericentriolar material ...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 / pericentriolar material / NAD+-protein mono-ADP-ribosyltransferase activity / NAD+ 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 / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Ankyrin repeat / 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 repeat / 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
Similarity search - Domain/homology
: / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.801 Å
AuthorsBosetti, C. / Paakkonen, J. / Lehtio, L.
Funding support Finland, 1items
OrganizationGrant numberCountry
Jane and Aatos Erkko Foundation Finland
CitationJournal: Eur.J.Med.Chem. / Year: 2025
Title: Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors.
Authors: Bosetti, C. / Kampasis, D. / Brinch, S.A. / Galera-Prat, A. / Karelou, M. / Dhakar, S.S. / Alaviuhkola, J. / Waaler, J. / Lehtio, L. / Kostakis, I.K.
History
DepositionFeb 26, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Poly [ADP-ribose] polymerase tankyrase-2
B: Poly [ADP-ribose] polymerase tankyrase-2
C: Poly [ADP-ribose] polymerase tankyrase-2
D: Poly [ADP-ribose] polymerase tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,97013
Polymers49,6924
Non-polymers1,2789
Water3,135174
1
A: Poly [ADP-ribose] polymerase tankyrase-2
B: Poly [ADP-ribose] polymerase tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,5317
Polymers24,8462
Non-polymers6855
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Poly [ADP-ribose] polymerase tankyrase-2
D: Poly [ADP-ribose] polymerase tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,4396
Polymers24,8462
Non-polymers5934
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)90.419, 98.162, 119.579
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-1326-

HOH

21C-1324-

HOH

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Components

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Poly [ADP-ribose] polymerase tankyrase- ... , 2 types, 4 molecules ACBD

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


Mass: 19482.053 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Chymotrypsin was included in the crystallization mixture. Consequently, there aren't missing residues, but a cut in the protein chain.
Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Production host: Escherichia coli (E. coli)
References: UniProt: Q9H2K2, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Protein/peptide Poly [ADP-ribose] polymerase tankyrase-2 / ADP-ribosyltransferase diphtheria toxin-like 6 / ARTD6 / Poly [ADP-ribose] polymerase 5B / Protein ...ADP-ribosyltransferase diphtheria toxin-like 6 / ARTD6 / Poly [ADP-ribose] polymerase 5B / Protein poly-ADP-ribosyltransferase tankyrase-2 / TNKS-2 / TRF1-interacting ankyrin-related ADP-ribose polymerase 2 / Tankyrase II / Tankyrase-2 / TANK2 / Tankyrase-like protein / Tankyrase-related protein


Mass: 5364.037 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Chymotrypsin was included in the crystallization mixture. Consequently, there aren't missing residues, but a cut in the protein chain.
Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Production host: Escherichia coli (E. coli)
References: UniProt: Q9H2K2, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases

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Non-polymers , 5 types, 183 molecules

#3: Chemical ChemComp-A1H5B / 8-nitro-2-[4-(trifluoromethyl)phenyl]-3H-quinazolin-4-one


Mass: 335.238 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H8F3N3O3 / Feature type: SUBJECT OF INVESTIGATION
#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.: 174 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.67 Å3/Da / Density % sol: 53.96 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 100 mM Tris pH 8.5, 22% PEG3350, 200 mM Li2SO4, 250 mM NaCl, 20% glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.920013 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 1, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.920013 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 49407 / % possible obs: 100 % / Redundancy: 13.54 % / CC1/2: 0.999 / Rmerge(I) obs: 0.079 / Rrim(I) all: 0.082 / Net I/σ(I): 17.75
Reflection shellResolution: 1.8→1.91 Å / Redundancy: 13.88 % / Rmerge(I) obs: 0.991 / Mean I/σ(I) obs: 2.11 / Num. unique obs: 7875 / CC1/2: 0.876 / Rrim(I) all: 1.029 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.801→42.324 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.957 / SU B: 2.5 / SU ML: 0.076 / Cross valid method: FREE R-VALUE / ESU R: 0.11 / ESU R Free: 0.109
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2147 2471 5.001 %
Rwork0.1808 46935 -
all0.183 --
obs-49406 99.953 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 36.444 Å2
Baniso -1Baniso -2Baniso -3
1--0.394 Å2-0 Å20 Å2
2---1.605 Å2-0 Å2
3---1.999 Å2
Refinement stepCycle: LAST / Resolution: 1.801→42.324 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3341 0 76 174 3591
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0133512
X-RAY DIFFRACTIONr_bond_other_d0.0010.0153146
X-RAY DIFFRACTIONr_angle_refined_deg1.4021.6414739
X-RAY DIFFRACTIONr_angle_other_deg1.3011.587233
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6925417
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.9521.196209
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.04215574
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7841528
X-RAY DIFFRACTIONr_chiral_restr0.0670.2421
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024019
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02891
X-RAY DIFFRACTIONr_nbd_refined0.1930.2567
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1740.22842
X-RAY DIFFRACTIONr_nbtor_refined0.1640.21662
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0710.21620
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1250.2164
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1710.28
X-RAY DIFFRACTIONr_nbd_other0.1790.234
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1690.214
X-RAY DIFFRACTIONr_mcbond_it2.6393.6241668
X-RAY DIFFRACTIONr_mcbond_other2.6373.6221667
X-RAY DIFFRACTIONr_mcangle_it3.7725.4092079
X-RAY DIFFRACTIONr_mcangle_other3.7715.4112080
X-RAY DIFFRACTIONr_scbond_it3.3774.0251843
X-RAY DIFFRACTIONr_scbond_other3.3544.0131828
X-RAY DIFFRACTIONr_scangle_it5.2355.8832658
X-RAY DIFFRACTIONr_scangle_other5.2095.8632635
X-RAY DIFFRACTIONr_lrange_it6.98441.1243827
X-RAY DIFFRACTIONr_lrange_other6.9841.0113808
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.801-1.8480.2931810.2633434X-RAY DIFFRACTION99.8895
1.848-1.8990.2561750.2423326X-RAY DIFFRACTION100
1.899-1.9540.2441720.2213260X-RAY DIFFRACTION100
1.954-2.0140.2341670.2013180X-RAY DIFFRACTION100
2.014-2.080.2391620.1893071X-RAY DIFFRACTION100
2.08-2.1530.221560.1792972X-RAY DIFFRACTION99.968
2.153-2.2340.2261510.1832873X-RAY DIFFRACTION100
2.234-2.3250.1951460.1682769X-RAY DIFFRACTION100
2.325-2.4280.2251390.1752635X-RAY DIFFRACTION100
2.428-2.5470.2181340.1852544X-RAY DIFFRACTION99.9627
2.547-2.6850.2161280.1982437X-RAY DIFFRACTION100
2.685-2.8470.2151200.1872292X-RAY DIFFRACTION100
2.847-3.0440.2231150.1842181X-RAY DIFFRACTION100
3.044-3.2880.2281060.1952013X-RAY DIFFRACTION100
3.288-3.6010.221990.1841871X-RAY DIFFRACTION100
3.601-4.0260.219880.1681682X-RAY DIFFRACTION100
4.026-4.6480.178800.1451507X-RAY DIFFRACTION100
4.648-5.690.156680.1521298X-RAY DIFFRACTION100
5.69-8.0380.256530.1941013X-RAY DIFFRACTION100
8.038-42.3240.222310.195578X-RAY DIFFRACTION97.2843

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