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- PDB-5nsp: Crystal structure of TNKS2 in complex with OD334 -

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Basic information

Entry
Database: PDB / ID: 5nsp
TitleCrystal structure of TNKS2 in complex with OD334
Components(Tankyrase-2) x 2
KeywordsTRANSFERASE / TNKS2 / ARTD6 / inhibitor / PARP5b / ADP-ribosyltransferase
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
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) ...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 / Special / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-97E / BICARBONATE ION / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsNkizinkiko, Y. / Haikarainen, T. / Lehtio, L.
Funding support Finland, 1items
OrganizationGrant numberCountry
Biocenter Oulu Finland
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach.
Authors: Anumala, U.R. / Waaler, J. / Nkizinkiko, Y. / Ignatev, A. / Lazarow, K. / Lindemann, P. / Olsen, P.A. / Murthy, S. / Obaji, E. / Majouga, A.G. / Leonov, S. / von Kries, J.P. / Lehtio, L. / ...Authors: Anumala, U.R. / Waaler, J. / Nkizinkiko, Y. / Ignatev, A. / Lazarow, K. / Lindemann, P. / Olsen, P.A. / Murthy, S. / Obaji, E. / Majouga, A.G. / Leonov, S. / von Kries, J.P. / Lehtio, L. / Krauss, S. / Nazare, M.
History
DepositionApr 26, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 29, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.3Jan 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
C: Tankyrase-2
B: Tankyrase-2
D: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,85614
Polymers54,6364
Non-polymers1,22010
Water1,62190
1
A: Tankyrase-2
C: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,7287
Polymers27,3182
Non-polymers4115
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6820 Å2
ΔGint-70 kcal/mol
Surface area10610 Å2
MethodPISA
2
B: Tankyrase-2
D: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1277
Polymers27,3182
Non-polymers8095
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6940 Å2
ΔGint-67 kcal/mol
Surface area10570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.060, 98.140, 119.510
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-1322-

HOH

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

#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
Details: Fragment: CATALYTIC DOMAIN, RESIDUES 946-1162 / 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
Details: Fragment: CATALYTIC DOMAIN, RESIDUES 946-1162 / 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 , 6 types, 100 molecules

#3: Chemical ChemComp-ZN / ZINC ION


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


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


Mass: 61.017 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: CHO3 / Comment: pH buffer*YM
#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: Chemical ChemComp-97E / 1-[4-[4-(2-chlorophenyl)-5-pyrimidin-4-yl-1,2,4-triazol-3-yl]phenyl]-2-oxidanylidene-3~{H}-benzimidazole-5-carbonitrile


Mass: 490.903 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H15ClN8O
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 90 / 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: 2.33 Å3/Da / Density % sol: 47.32 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 24%/26% PEG3350, 0.2M Lithium sulfate, 0.1M Tris-HCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 2, 2014
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.3→45.39 Å / Num. obs: 23860 / % possible obs: 100 % / Observed criterion σ(I): 1.76 / Redundancy: 6.7 % / Rmerge(I) obs: 0.198 / Net I/σ(I): 8.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3U9H

3u9h


Resolution: 2.3→45.39 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.91 / SU B: 8.128 / SU ML: 0.185 / Cross valid method: THROUGHOUT / ESU R: 0.285 / ESU R Free: 0.228 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24717 1193 5 %RANDOM
Rwork0.18997 ---
obs0.19289 22667 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.764 Å2
Baniso -1Baniso -2Baniso -3
1--0.68 Å2-0 Å20 Å2
2---1.08 Å2-0 Å2
3---1.76 Å2
Refinement stepCycle: 1 / Resolution: 2.3→45.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3349 0 72 90 3511
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0193517
X-RAY DIFFRACTIONr_bond_other_d0.0020.023088
X-RAY DIFFRACTIONr_angle_refined_deg1.7351.9534740
X-RAY DIFFRACTIONr_angle_other_deg1.0073.0017156
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9065417
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.1922.818181
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.25415579
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4381529
X-RAY DIFFRACTIONr_chiral_restr0.10.2471
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023958
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02790
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_it2.8323.4121668
X-RAY DIFFRACTIONr_mcbond_other2.8273.411667
X-RAY DIFFRACTIONr_mcangle_it4.3815.0952079
X-RAY DIFFRACTIONr_mcangle_other4.385.0972080
X-RAY DIFFRACTIONr_scbond_it3.3453.8261849
X-RAY DIFFRACTIONr_scbond_other3.3343.8251843
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.2765.5932654
X-RAY DIFFRACTIONr_long_range_B_refined7.64538.7083760
X-RAY DIFFRACTIONr_long_range_B_other7.64438.7083761
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.403 86 -
Rwork0.309 1634 -
obs--99.88 %

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