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- PDB-4u6a: X-ray crystal structure of human TNKS in complex with a small mol... -

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Basic information

Entry
Database: PDB / ID: 4u6a
TitleX-ray crystal structure of human TNKS in complex with a small molecule inhibitor
ComponentsTankyrase-1
KeywordsTRANSFERASE / Inhibitor / WNT signalling
Function / homology
Function and homology information


negative regulation of telomeric DNA binding / negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric / regulation of telomere maintenance via telomerase / XAV939 stabilizes AXIN / NAD+ ADP-ribosyltransferase / protein localization to chromosome, telomeric region / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein poly-ADP-ribosylation / pericentriolar material ...negative regulation of telomeric DNA binding / negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric / regulation of telomere maintenance via telomerase / XAV939 stabilizes AXIN / NAD+ ADP-ribosyltransferase / protein localization to chromosome, telomeric region / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / protein poly-ADP-ribosylation / pericentriolar material / mitotic spindle pole / positive regulation of telomere capping / NAD+-protein ADP-ribosyltransferase activity / NAD+ ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / spindle assembly / mRNA transport / nuclear pore / positive regulation of telomerase activity / positive regulation of telomere maintenance via telomerase / nucleotidyltransferase activity / mitotic spindle organization / TCF dependent signaling in response to WNT / Degradation of AXIN / peptidyl-threonine phosphorylation / Wnt signaling pathway / Regulation of PTEN stability and activity / protein polyubiquitination / positive regulation of canonical Wnt signaling pathway / protein transport / histone binding / peptidyl-serine phosphorylation / nuclear membrane / chromosome, telomeric region / nuclear body / Ub-specific processing proteases / cell division / Golgi membrane / Golgi apparatus / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Phosphoenolpyruvate Carboxykinase; domain 3 - #10 / Phosphoenolpyruvate Carboxykinase; domain 3 / Ankyrin repeats (many copies) / 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 ...Phosphoenolpyruvate Carboxykinase; domain 3 - #10 / Phosphoenolpyruvate Carboxykinase; domain 3 / Ankyrin repeats (many copies) / 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 / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-3DN / Poly [ADP-ribose] polymerase tankyrase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.37 Å
AuthorsOliver, A.W.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome TrustSDDI United Kingdom
CitationJournal: To be published
Title: Design and discovery of 3-aryl-5-substituted-isoquinolin-1- ones as potent and selective tankyrase inhibitors
Authors: Elliot, R.J. / Jarvis, A. / Rajasekaran, M.B. / Menon, M. / Bowers, L. / Boffey, R. / Bayford, M. / Firth-Clark, S. / Beevers, R. / Aquil, R. / Kirton, S.B. / Niculescu-Duvaz, D. / Fish, L. ...Authors: Elliot, R.J. / Jarvis, A. / Rajasekaran, M.B. / Menon, M. / Bowers, L. / Boffey, R. / Bayford, M. / Firth-Clark, S. / Beevers, R. / Aquil, R. / Kirton, S.B. / Niculescu-Duvaz, D. / Fish, L. / Lopes, F. / McLeary, R. / Trindade, I. / Vendrell, E. / Munkonge, F. / Porter, R. / Perrior, T. / Springer, C. / Oliver, A.W. / Pearl, L.H. / Ashworth, A. / Lord, C.J.
History
DepositionJul 28, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jul 8, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 15, 2015Group: Other
Revision 1.2Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_special_symmetry
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-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,44310
Polymers29,4171
Non-polymers1,0269
Water1,69394
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1270 Å2
ΔGint-0 kcal/mol
Surface area10760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.380, 80.980, 84.020
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number24
Space group name H-MI212121
Components on special symmetry positions
IDModelComponents
11A-1407-

GOL

21A-1408-

EDO

31A-1409-

GOL

41A-1409-

GOL

51A-1523-

HOH

Detailsbiological unit is the same as asym.

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Tankyrase-1 / / TANK1 / ADP-ribosyltransferase diphtheria toxin-like 5 / ARTD5 / Poly [ADP-ribose] polymerase 5A / ...TANK1 / ADP-ribosyltransferase diphtheria toxin-like 5 / ARTD5 / Poly [ADP-ribose] polymerase 5A / TNKS-1 / TRF1-interacting ankyrin-related ADP-ribose polymerase / Tankyrase I


Mass: 29417.082 Da / Num. of mol.: 1 / Fragment: UNP residues 1091-1325
Source method: isolated from a genetically manipulated source
Details: Catalytic Domain / Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS, PARP5A, PARPL, TIN1, TINF1, TNKS1 / Plasmid: pNic-Bsa4-TNKS1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): Rosetta2 / References: UniProt: O95271, NAD+ ADP-ribosyltransferase

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Non-polymers , 5 types, 103 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-3DN / 3-(4-{[4-(dimethylamino)piperidin-1-yl]methyl}phenyl)-5-methylisoquinolin-1(2H)-one


Mass: 375.507 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H29N3O
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 2.35 Å3/Da / Density % sol: 47.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.1 M MES pH 6.0, 0.1 M ammonium tartrate, 12-16% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97939 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97939 Å / Relative weight: 1
ReflectionResolution: 2.37→58.31 Å / Num. obs: 11373 / % possible obs: 98.3 % / Redundancy: 4 % / Biso Wilson estimate: 50.5 Å2 / Net I/σ(I): 8.4
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
2.37-2.430.5780.9181.533354159314951.17893.8
2.43-2.50.6390.8381.913263157214811.08494.2
2.5-2.570.640.7682.063110151414321.00294.6
2.57-2.650.5850.7092.563008150613910.92692.4
2.65-2.740.8140.483.33111143914050.62397.6
2.74-2.830.840.383.872919138213480.49997.5
2.83-2.940.8710.3054.242851135213100.496.9
2.94-3.060.8890.2654.982778126712320.34797.2
3.06-3.20.9350.2085.62675124011880.27195.8
3.2-3.350.9630.1386.982405119611150.18293.2
3.35-3.530.9770.1127.942438114710980.14795.7
3.53-3.750.9840.0939.052246107310310.12196.1
3.75-4.010.9890.06810.7719629729040.08993
4.01-4.330.9920.06112.2320079488890.07993.8
4.33-4.740.9890.05613.8616828607740.07390
4.74-5.30.9910.05313.9616307557220.06895.6
5.3-6.120.9950.0512.6914326886620.06596.2
6.12-7.490.9950.04713.9112935855680.06197.1
7.49-10.60.9970.03617.39444504300.04795.6
10.60.9960.03417.974972442310.04594.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimless0.3.5data scaling
PDB_EXTRACT3.14data extraction
PHASER2.5.6phasing
XSCALEdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2RF5

2rf5


Resolution: 2.37→58.31 Å / Cor.coef. Fo:Fc: 0.8966 / Cor.coef. Fo:Fc free: 0.8759 / SU R Cruickshank DPI: 0.3 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.32 / SU Rfree Blow DPI: 0.238 / SU Rfree Cruickshank DPI: 0.235
RfactorNum. reflection% reflectionSelection details
Rfree0.248 581 5.11 %RANDOM
Rwork0.191 ---
obs0.194 11373 98.04 %-
Displacement parametersBiso mean: 46.03 Å2
Baniso -1Baniso -2Baniso -3
1-6.4564 Å20 Å20 Å2
2--19.4294 Å20 Å2
3----25.8858 Å2
Refine analyzeLuzzati coordinate error obs: 0.309 Å
Refinement stepCycle: 1 / Resolution: 2.37→58.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1645 0 67 94 1806
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011750HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.052346HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d796SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes39HARMONIC2
X-RAY DIFFRACTIONt_gen_planes280HARMONIC5
X-RAY DIFFRACTIONt_it1750HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.41
X-RAY DIFFRACTIONt_other_torsion3.47
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion210SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_utility_distance7HARMONIC1
X-RAY DIFFRACTIONt_utility_angle6HARMONIC1
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1980SEMIHARMONIC4
LS refinement shellResolution: 2.37→2.6 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.3608 124 4.71 %
Rwork0.2459 2510 -
all0.251 2634 -
obs--98.04 %

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