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- PDB-7r5x: Tankyrase 2 in complex with an inhibitor (OUL211) -

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Basic information

Entry
Database: PDB / ID: 7r5x
TitleTankyrase 2 in complex with an inhibitor (OUL211)
Components(Poly [ADP-ribose] polymerase tankyrase- ...) x 2
KeywordsTRANSFERASE / Inhibitor / Complex / ADP-ribosylation / Enzyme
Function / homology
Function and homology information


XAV939 stabilizes AXIN / positive regulation of telomere capping / NAD+ ADP-ribosyltransferase / protein auto-ADP-ribosylation / protein localization to chromosome, telomeric region / negative regulation of telomere maintenance via telomere lengthening / 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 / protein auto-ADP-ribosylation / protein localization to chromosome, telomeric region / negative regulation of telomere maintenance via telomere lengthening / 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 / nuclear envelope / positive regulation of canonical Wnt signaling pathway / 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
7-methyl-[1,2,4]triazolo[3,4-b][1,3]benzothiazole / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.052 Å
AuthorsSowa, S.T. / Lehtio, L.
Funding support Finland, 2items
OrganizationGrant numberCountry
Academy of Finland287063 Finland
Academy of Finland294085 Finland
CitationJournal: J.Med.Chem. / Year: 2023
Title: [1,2,4]Triazolo[3,4- b ]benzothiazole Scaffold as Versatile Nicotinamide Mimic Allowing Nanomolar Inhibition of Different PARP Enzymes.
Authors: Murthy, S. / Nizi, M.G. / Maksimainen, M.M. / Massari, S. / Alaviuhkola, J. / Lippok, B.E. / Vagaggini, C. / Sowa, S.T. / Galera-Prat, A. / Ashok, Y. / Venkannagari, H. / Prunskaite- ...Authors: Murthy, S. / Nizi, M.G. / Maksimainen, M.M. / Massari, S. / Alaviuhkola, J. / Lippok, B.E. / Vagaggini, C. / Sowa, S.T. / Galera-Prat, A. / Ashok, Y. / Venkannagari, H. / Prunskaite-Hyyrylainen, R. / Dreassi, E. / Luscher, B. / Korn, P. / Tabarrini, O. / Lehtio, L.
History
DepositionFeb 11, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 8, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)50,67813
Polymers49,6924
Non-polymers9869
Water3,045169
1
AAA: Poly [ADP-ribose] polymerase tankyrase-2
A: Poly [ADP-ribose] polymerase tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,3857
Polymers24,8462
Non-polymers5395
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
BBB: Poly [ADP-ribose] polymerase tankyrase-2
B: Poly [ADP-ribose] polymerase tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,2936
Polymers24,8462
Non-polymers4474
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)91.940, 96.990, 119.440
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
11AAA-1353-

HOH

21BBB-1319-

HOH

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Components

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

#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, 178 molecules

#3: Chemical ChemComp-I6D / 7-methyl-[1,2,4]triazolo[3,4-b][1,3]benzothiazole


Mass: 189.237 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H7N3S / 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.: 169 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.68 Å3/Da / Density % sol: 54.12 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: 100 mM Tris pH=8.5, 200mM Lithium Sulphate, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.92023 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jun 25, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92023 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 36379 / % possible obs: 99.93 % / Redundancy: 7.9 % / CC1/2: 0.998 / Net I/σ(I): 15.2
Reflection shellResolution: 2→2.072 Å / Num. unique obs: 3591 / CC1/2: 0.871

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5OWS

5ows


Resolution: 2.052→48.542 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.942 / SU B: 3.736 / SU ML: 0.104 / Cross valid method: FREE R-VALUE / ESU R: 0.164 / ESU R Free: 0.148
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2244 1819 5 %
Rwork0.1887 34559 -
all0.191 --
obs-36378 99.94 %
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: 35.436 Å2
Baniso -1Baniso -2Baniso -3
1-0.162 Å2-0 Å2-0 Å2
2---0.446 Å2-0 Å2
3---0.284 Å2
Refinement stepCycle: LAST / Resolution: 2.052→48.542 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3354 0 54 169 3577
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0133553
X-RAY DIFFRACTIONr_bond_other_d0.0010.0153210
X-RAY DIFFRACTIONr_angle_refined_deg1.3581.6444799
X-RAY DIFFRACTIONr_angle_other_deg1.2411.587384
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7575431
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.04821.028214
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.03715587
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2581530
X-RAY DIFFRACTIONr_chiral_restr0.0590.2426
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024099
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02905
X-RAY DIFFRACTIONr_nbd_refined0.1890.2595
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1710.22841
X-RAY DIFFRACTIONr_nbtor_refined0.1610.21647
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0710.21574
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1420.2182
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1610.214
X-RAY DIFFRACTIONr_nbd_other0.1960.255
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1140.211
X-RAY DIFFRACTIONr_mcbond_it2.2653.5821700
X-RAY DIFFRACTIONr_mcbond_other2.2653.581699
X-RAY DIFFRACTIONr_mcangle_it3.3955.3492127
X-RAY DIFFRACTIONr_mcangle_other3.3945.3512128
X-RAY DIFFRACTIONr_scbond_it2.6783.9161852
X-RAY DIFFRACTIONr_scbond_other2.6713.9071837
X-RAY DIFFRACTIONr_scangle_it4.2975.7482668
X-RAY DIFFRACTIONr_scangle_other4.2955.7342645
X-RAY DIFFRACTIONr_lrange_it6.19141.0893849
X-RAY DIFFRACTIONr_lrange_other6.14741.0013830
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.0520.2881320.2452511X-RAY DIFFRACTION100
2.052-2.1080.2721310.2272486X-RAY DIFFRACTION100
2.108-2.1690.2521260.2142394X-RAY DIFFRACTION100
2.169-2.2360.2421220.2072326X-RAY DIFFRACTION100
2.236-2.3090.2551200.2022277X-RAY DIFFRACTION100
2.309-2.390.2361150.192186X-RAY DIFFRACTION100
2.39-2.4810.2451110.1952118X-RAY DIFFRACTION100
2.481-2.5820.2631070.1952027X-RAY DIFFRACTION99.8596
2.582-2.6970.2441020.2141938X-RAY DIFFRACTION99.951
2.697-2.8280.227980.1961853X-RAY DIFFRACTION99.9488
2.828-2.9810.241940.1971801X-RAY DIFFRACTION100
2.981-3.1620.199900.1891695X-RAY DIFFRACTION100
3.162-3.380.21830.1981588X-RAY DIFFRACTION99.8805
3.38-3.650.236780.1871486X-RAY DIFFRACTION99.9361
3.65-3.9980.231730.1681378X-RAY DIFFRACTION99.9311
3.998-4.470.163660.1561254X-RAY DIFFRACTION99.8487
4.47-5.160.177580.1551106X-RAY DIFFRACTION99.8285
5.16-6.3170.314500.194941X-RAY DIFFRACTION99.598
6.317-8.9210.174390.19750X-RAY DIFFRACTION100

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