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- PDB-8b6m: Tankyrase 2 in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 8b6m
TitleTankyrase 2 in complex with an inhibitor
Components(Poly [ADP-ribose] polymerase tankyrase- ...) x 2
KeywordsTRANSFERASE / Inhibitor
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 / Regulation of PTEN stability and activity / Wnt signaling pathway / 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
Chem-OY6 / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsBosetti, C. / Sowa, S.T. / Lehtio, L.
Funding support Finland, 1items
OrganizationGrant numberCountry
Jane and Aatos Erkko Foundation Finland
CitationJournal: J.Med.Chem. / Year: 2025
Title: Deconstruction of Dual-Site Tankyrase Inhibitors Provides Insights into Binding Energetics and Suggests Critical Hotspots for Ligand Optimization.
Authors: Sowa, S.T. / Kucukdisli, M. / Mostinski, Y. / Schaller, D.A. / Vinagreiro, C.S. / Cirillo, D. / Bosetti, C. / Brinch, S.A. / van Laar, K. / Wegert, A. / Leenders, R.G.G. / Krauss, S. / ...Authors: Sowa, S.T. / Kucukdisli, M. / Mostinski, Y. / Schaller, D.A. / Vinagreiro, C.S. / Cirillo, D. / Bosetti, C. / Brinch, S.A. / van Laar, K. / Wegert, A. / Leenders, R.G.G. / Krauss, S. / Waaler, J. / Volkamer, A. / Lehtio, L. / Nazare, M.
History
DepositionSep 27, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2025Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
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 / _pdbx_entry_details.has_protein_modification

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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)51,40713
Polymers49,6924
Non-polymers1,7149
Water3,603200
1
A: Poly [ADP-ribose] polymerase tankyrase-2
B: Poly [ADP-ribose] polymerase tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,7497
Polymers24,8462
Non-polymers9035
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)25,6576
Polymers24,8462
Non-polymers8114
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)90.570, 97.370, 119.240
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-1336-

HOH

21C-1319-

HOH

31D-1317-

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
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
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, 209 molecules

#3: Chemical ChemComp-OY6 / ~{N}-(2-methoxyphenyl)-4-[[2-(4-oxidanylidene-3~{H}-quinazolin-2-yl)ethyl-(thiophen-2-ylmethyl)carbamoyl]amino]benzamide


Mass: 553.631 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H27N5O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#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.: 200 / 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: 2.65 Å3/Da / Density % sol: 53.5 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 100 mM Tris, 22% w/v PEG3350, 200 mM Li2SO4, 250 mM NaCl, 20% v/v glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.96546 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Jun 6, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96546 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. obs: 69406 / % possible obs: 99.7 % / Redundancy: 5.5 % / CC1/2: 0.999 / Net I/σ(I): 15.99
Reflection shellResolution: 1.6→1.64 Å / Num. unique obs: 5106 / CC1/2: 0.648

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7OM1

7om1


Resolution: 1.6→48.685 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.949 / WRfactor Rfree: 0.222 / WRfactor Rwork: 0.19 / SU B: 1.725 / SU ML: 0.059 / Average fsc free: 0.9645 / Average fsc work: 0.9736 / Cross valid method: FREE R-VALUE / ESU R: 0.081 / ESU R Free: 0.085
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2194 3471 5.001 %
Rwork0.1849 65934 -
all0.187 --
obs-69405 99.69 %
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: 27.2 Å2
Baniso -1Baniso -2Baniso -3
1--0.31 Å2-0 Å2-0 Å2
2---0.679 Å2-0 Å2
3---0.989 Å2
Refinement stepCycle: LAST / Resolution: 1.6→48.685 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3308 0 108 200 3616
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0123607
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163108
X-RAY DIFFRACTIONr_angle_refined_deg1.8741.6994872
X-RAY DIFFRACTIONr_angle_other_deg0.6121.5987254
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8745432
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.383529
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.1310589
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.80610181
X-RAY DIFFRACTIONr_chiral_restr0.0790.2478
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.024191
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02793
X-RAY DIFFRACTIONr_nbd_refined0.2230.2595
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1990.23005
X-RAY DIFFRACTIONr_nbtor_refined0.1810.21723
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0840.21823
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1330.2178
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2130.219
X-RAY DIFFRACTIONr_nbd_other0.1530.265
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1040.232
X-RAY DIFFRACTIONr_mcbond_it2.4962.7551695
X-RAY DIFFRACTIONr_mcbond_other2.4882.7541695
X-RAY DIFFRACTIONr_mcangle_it3.5534.1142126
X-RAY DIFFRACTIONr_mcangle_other3.5534.1152127
X-RAY DIFFRACTIONr_scbond_it3.2973.0951912
X-RAY DIFFRACTIONr_scbond_other3.2793.0861893
X-RAY DIFFRACTIONr_scangle_it4.9084.5272742
X-RAY DIFFRACTIONr_scangle_other4.894.512713
X-RAY DIFFRACTIONr_lrange_it6.52335.9144002
X-RAY DIFFRACTIONr_lrange_other6.49435.1313968
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.6-1.6420.3862550.36848410.36951000.9290.9499.92160.339
1.642-1.6860.3632490.29347300.29649790.9410.9551000.253
1.686-1.7350.2642410.23945790.24148220.9580.96699.95850.199
1.735-1.7890.2252340.21444400.21546760.970.97299.95720.177
1.789-1.8470.2252300.20343760.20446060.9660.9741000.17
1.847-1.9120.2222180.18941350.1943580.9690.97799.88530.161
1.912-1.9840.2222130.18940440.19142610.970.97899.90610.166
1.984-2.0650.2132050.1839100.18241230.9740.98199.8060.164
2.065-2.1570.2141970.17737320.17839400.9750.98299.72080.163
2.157-2.2620.2351870.18435610.18637690.9670.9899.44280.174
2.262-2.3840.2091790.17934010.1835900.9710.98199.72150.171
2.384-2.5280.221700.17632260.17834070.9710.98299.67710.175
2.528-2.7020.2311590.18730210.1931880.9680.97999.74910.191
2.702-2.9180.2041490.17628390.17729960.9720.98199.7330.186
2.918-3.1950.211380.18726060.18827580.9720.97999.49240.202
3.195-3.570.2321240.17723710.1825140.970.98299.24420.198
3.57-4.1190.1971110.16420980.16522360.9730.98498.79250.197
4.119-5.0350.18930.14817750.14919000.9810.98998.31580.187
5.035-7.0830.196750.19714170.19714990.9780.98299.5330.236
7.083-48.6850.251440.2178320.2198960.9470.97497.76790.271

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