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- PDB-8s4w: Tankyrase 2 in complex with a quinazolin-4-one inhibitor -

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Basic information

Entry
Database: PDB / ID: 8s4w
TitleTankyrase 2 in complex with a quinazolin-4-one inhibitor
Components(Poly [ADP-ribose] polymerase tankyrase- ...) x 2
KeywordsTRANSFERASE / Inhibitor / 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 / 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
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: 2.12 Å
AuthorsBosetti, C. / 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 22, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 5, 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
E: Poly [ADP-ribose] polymerase tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,4856
Polymers24,8462
Non-polymers6394
Water1,54986
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6430 Å2
ΔGint-65 kcal/mol
Surface area10230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.600, 66.600, 120.586
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2
Components on special symmetry positions
IDModelComponents
11A-1319-

HOH

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Components

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

#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.: 1
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.: 1
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 , 4 types, 90 molecules

#3: Chemical ChemComp-A1H44 / (2~{R})-~{N}-[2-(4-~{tert}-butylphenyl)-4-oxidanylidene-3~{H}-quinazolin-8-yl]-2,3-bis(oxidanyl)propanamide


Mass: 381.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 2.69 Å3/Da / Density % sol: 54.32 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
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: ESRF / Beamline: MASSIF-3 / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Nov 21, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 2.12→50 Å / Num. obs: 16027 / % possible obs: 99.5 % / Redundancy: 12.659 % / Biso Wilson estimate: 43.67 Å2 / CC1/2: 0.997 / Net I/σ(I): 10.11
Reflection shellResolution: 2.12→2.25 Å / Num. unique obs: 33204 / CC1/2: 0.797

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.12→44.7 Å / SU ML: 0.3526 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.9146
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2464 801 5 %
Rwork0.1892 15206 -
obs0.1922 16007 99.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 48.37 Å2
Refinement stepCycle: LAST / Resolution: 2.12→44.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1672 0 39 86 1797
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01151759
X-RAY DIFFRACTIONf_angle_d1.11612373
X-RAY DIFFRACTIONf_chiral_restr0.0552232
X-RAY DIFFRACTIONf_plane_restr0.0092310
X-RAY DIFFRACTIONf_dihedral_angle_d14.3046639
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.12-2.250.36341280.30452410X-RAY DIFFRACTION96.54
2.25-2.420.31291300.30382484X-RAY DIFFRACTION99.77
2.42-2.670.31171320.23562505X-RAY DIFFRACTION99.96
2.67-3.050.32511330.22562529X-RAY DIFFRACTION99.92
3.05-3.850.25621340.17362561X-RAY DIFFRACTION99.96
3.85-44.70.16881440.14242717X-RAY DIFFRACTION99.9

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