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- PDB-6tks: Tankyrase 2 in complex with an inhibitor (OM-1720) -

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Basic information

Entry
Database: PDB / ID: 6tks
TitleTankyrase 2 in complex with an inhibitor (OM-1720)
ComponentsTankyrase-2
KeywordsTRANSFERASE / Inhibitor / Complex / Poly-ADP-ribosylation / Enzyme
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
Chem-NJ2 / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsSowa, S.T. / Lehtio, L.
Funding support Finland, 2items
OrganizationGrant numberCountry
Academy of Finland287063, 294085 Finland
Jane and Aatos Erkko Foundation Finland
CitationJournal: J.Med.Chem. / Year: 2020
Title: Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.
Authors: Waaler, J. / Leenders, R.G.G. / Sowa, S.T. / Alam Brinch, S. / Lycke, M. / Nieczypor, P. / Aertssen, S. / Murthy, S. / Galera-Prat, A. / Damen, E. / Wegert, A. / Nazare, M. / Lehtio, L. / Krauss, S.
History
DepositionNov 28, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 24, 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

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Assembly

Deposited unit
AAA: Tankyrase-2
BBB: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,7496
Polymers54,6002
Non-polymers1,1504
Water66737
1
AAA: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,8753
Polymers27,3001
Non-polymers5752
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
BBB: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,8753
Polymers27,3001
Non-polymers5752
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.600, 76.420, 148.190
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain: (Details: Chains A B)

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Components

#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: 27299.764 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: Chemical ChemComp-NJ2 / ~{N}-[3-[5-(5-ethoxypyridin-2-yl)-4-(2-fluorophenyl)-1,2,4-triazol-3-yl]cyclobutyl]-1,6-naphthyridine-2-carboxamide


Mass: 509.534 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H24FN7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.16 Å3/Da / Density % sol: 42.98 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, sitting drop / Details: 7.5-25% PEG 6000, Bicine, pH=9.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Oct 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 16853 / % possible obs: 98.7 % / Redundancy: 5.392 % / CC1/2: 0.997 / Net I/σ(I): 9.91
Reflection shellResolution: 2.5→2.56 Å / Num. unique obs: 1257 / CC1/2: 0.954

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5NOB

5nob


Resolution: 2.5→41.519 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.925 / SU B: 13.293 / SU ML: 0.276 / Cross valid method: FREE R-VALUE / ESU R: 0.651 / ESU R Free: 0.305
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2592 843 5.002 %
Rwork0.2138 --
all0.216 --
obs-16853 98.677 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 53.242 Å2
Baniso -1Baniso -2Baniso -3
1-4.18 Å20 Å20 Å2
2--2.219 Å2-0 Å2
3----6.399 Å2
Refinement stepCycle: LAST / Resolution: 2.5→41.519 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3285 0 78 37 3400
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0133460
X-RAY DIFFRACTIONr_bond_other_d0.0020.0183021
X-RAY DIFFRACTIONr_angle_refined_deg1.2931.684668
X-RAY DIFFRACTIONr_angle_other_deg1.191.6016992
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.985408
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.25621.024205
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.48715551
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.1011528
X-RAY DIFFRACTIONr_chiral_restr0.0460.2417
X-RAY DIFFRACTIONr_chiral_restr_other1.4870.28
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023929
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02817
X-RAY DIFFRACTIONr_nbd_refined0.1780.2583
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1720.22779
X-RAY DIFFRACTIONr_nbtor_refined0.1620.21595
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0720.21574
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1080.294
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0090.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1510.210
X-RAY DIFFRACTIONr_nbd_other0.2640.236
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1150.24
X-RAY DIFFRACTIONr_mcbond_it2.7245.6511641
X-RAY DIFFRACTIONr_mcbond_other2.725.6491640
X-RAY DIFFRACTIONr_mcangle_it4.4998.4572043
X-RAY DIFFRACTIONr_mcangle_other4.4988.4582044
X-RAY DIFFRACTIONr_scbond_it2.7415.8931819
X-RAY DIFFRACTIONr_scbond_other2.745.8931820
X-RAY DIFFRACTIONr_scangle_it4.5198.7132620
X-RAY DIFFRACTIONr_scangle_other4.5188.7132621
X-RAY DIFFRACTIONr_lrange_it6.91962.7193699
X-RAY DIFFRACTIONr_lrange_other6.91862.7113700
X-RAY DIFFRACTIONr_ncsr_local_group_10.090.056369
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.5650.292630.3541191X-RAY DIFFRACTION99.2089
2.565-2.6350.374590.3521129X-RAY DIFFRACTION99.4975
2.635-2.7120.32580.3231101X-RAY DIFFRACTION99.6561
2.712-2.7950.408560.291064X-RAY DIFFRACTION99.115
2.795-2.8870.259550.2511046X-RAY DIFFRACTION99.3682
2.887-2.9880.269540.2181024X-RAY DIFFRACTION99.5383
2.988-3.1010.249510.218970X-RAY DIFFRACTION99.5127
3.101-3.2270.276510.207966X-RAY DIFFRACTION99.2195
3.227-3.3710.277470.204891X-RAY DIFFRACTION99.5754
3.371-3.5350.245450.221870X-RAY DIFFRACTION98.7055
3.535-3.7260.249410.235766X-RAY DIFFRACTION92.0182
3.726-3.9520.291410.209776X-RAY DIFFRACTION97.6105
3.952-4.2250.199390.177744X-RAY DIFFRACTION99.4917
4.225-4.5630.216360.162696X-RAY DIFFRACTION98.9189
4.563-4.9980.214340.175630X-RAY DIFFRACTION98.6627
4.998-5.5870.299300.199581X-RAY DIFFRACTION97.4482
5.587-6.450.276280.214524X-RAY DIFFRACTION98.3957
6.45-7.8950.244240.185460X-RAY DIFFRACTION99.1803
7.895-11.150.172190.155365X-RAY DIFFRACTION99.7403

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