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- PDB-6kro: Tankyrase-2 in complex with RK-582 -

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Basic information

Entry
Database: PDB / ID: 6kro
TitleTankyrase-2 in complex with RK-582
Components(Tankyrase-2) x 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Tankyrase / PARP / ADP-ribosylation / Transferase-transferase inhibitor complex
Function / homology
Function and homology information


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 / positive regulation of telomere capping / NAD+-protein ADP-ribosyltransferase activity / NAD+-protein poly-ADP-ribosyltransferase activity ...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 / positive regulation of telomere capping / NAD+-protein ADP-ribosyltransferase activity / NAD+-protein 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 / nucleus / metal ion binding / 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 / Ankyrin repeats (many copies) / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain ...YefM-like fold / YefM-like fold - #10 / : / Ankyrin repeat / Phosphoenolpyruvate Carboxykinase; domain 3 - #10 / Other non-globular / 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 / Special / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-DU9 / PHOSPHATE ION / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsNiwa, H. / Shirai, F. / Sato, S. / Tsumura, T. / Okue, M. / Shirouzu, M. / Seimiya, H. / Umehara, T.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer.
Authors: Shirai, F. / Mizutani, A. / Yashiroda, Y. / Tsumura, T. / Kano, Y. / Muramatsu, Y. / Chikada, T. / Yuki, H. / Niwa, H. / Sato, S. / Washizuka, K. / Koda, Y. / Mazaki, Y. / Jang, M.K. / ...Authors: Shirai, F. / Mizutani, A. / Yashiroda, Y. / Tsumura, T. / Kano, Y. / Muramatsu, Y. / Chikada, T. / Yuki, H. / Niwa, H. / Sato, S. / Washizuka, K. / Koda, Y. / Mazaki, Y. / Jang, M.K. / Yoshida, H. / Nagamori, A. / Okue, M. / Watanabe, T. / Kitamura, K. / Shitara, E. / Honma, T. / Umehara, T. / Shirouzu, M. / Fukami, T. / Seimiya, H. / Yoshida, M. / Koyama, H.
History
DepositionAug 22, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 1, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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
B: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,3707
Polymers24,5152
Non-polymers8555
Water2,036113
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6650 Å2
ΔGint-40 kcal/mol
Surface area10320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.116, 66.116, 114.758
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2
Components on special symmetry positions
IDModelComponents
11A-1328-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#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: 19150.621 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Production host: Cell-free synthesis (others)
References: UniProt: Q9H2K2, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Protein/peptide Tankyrase-2


Mass: 5364.037 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Production host: Cell-free synthesis (others) / References: UniProt: Q9H2K2

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Non-polymers , 5 types, 118 molecules

#3: Chemical ChemComp-DU9 / 6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-4-fluoranyl-1-methyl-1'-(8-methyl-4-oxidanylidene-3,5,6,7-tetrahydropyrido[2,3-d]pyrimidin-2-yl)spiro[indole-3,4'-piperidine]-2-one


Mass: 510.604 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C27H35FN6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 113 / 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: 2.58 Å3/Da / Density % sol: 52.32 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 0.1M Tris pH 8.5, 1.6M (NH4)2HPO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL26B2 / Wavelength: 1 Å
DetectorType: RAYONIX MX225-HS / Detector: CCD / Date: Feb 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→46.75 Å / Num. obs: 20832 / % possible obs: 100 % / Redundancy: 14.3 % / Biso Wilson estimate: 33.74 Å2 / CC1/2: 0.999 / Rpim(I) all: 0.03 / Rrim(I) all: 0.114 / Rsym value: 0.11 / Net I/σ(I): 16.3
Reflection shellResolution: 1.9→1.94 Å / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1317 / CC1/2: 0.615 / Rpim(I) all: 0.534 / Rrim(I) all: 2.047 / Rsym value: 1.975

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Processing

Software
NameVersionClassification
PHENIX1.13_2998+SVNrefinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→46.75 Å / SU ML: 0.2319 / Cross valid method: FREE R-VALUE / σ(F): 0.31 / Phase error: 20.4427
RfactorNum. reflection% reflection
Rfree0.2031 1968 5.14 %
Rwork0.1717 --
obs0.1733 20773 100 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 42.05 Å2
Refinement stepCycle: LAST / Resolution: 1.9→46.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1659 0 55 113 1827
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0111758
X-RAY DIFFRACTIONf_angle_d1.02772373
X-RAY DIFFRACTIONf_chiral_restr0.056233
X-RAY DIFFRACTIONf_plane_restr0.0061304
X-RAY DIFFRACTIONf_dihedral_angle_d19.01521017
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.950.30661430.29732650X-RAY DIFFRACTION100
1.95-20.2981480.26032552X-RAY DIFFRACTION100
2-2.060.26691650.24432576X-RAY DIFFRACTION100
2.06-2.130.27091340.22122595X-RAY DIFFRACTION100
2.13-2.20.29341570.21462588X-RAY DIFFRACTION100
2.2-2.290.24321450.19442570X-RAY DIFFRACTION100
2.29-2.390.22661440.18762586X-RAY DIFFRACTION100
2.39-2.520.18491480.1732591X-RAY DIFFRACTION100
2.52-2.680.25741420.18022609X-RAY DIFFRACTION100
2.68-2.880.21091540.16992562X-RAY DIFFRACTION100
2.88-3.170.23821160.16592632X-RAY DIFFRACTION100
3.17-3.630.16561200.15292603X-RAY DIFFRACTION100
3.63-4.580.15351350.12892610X-RAY DIFFRACTION100
4.58-46.750.17461170.17242624X-RAY DIFFRACTION99.96
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
15.90417067571-1.56155808270.01434256756944.238695631421.154017233963.713049261430.2604637867990.5272068693070.00369073442293-0.353569593811-0.2447494559290.677610316111-0.14398525841-0.448424753753-0.01375223346080.254361133015-0.0426107603509-0.02636862139630.3436890077080.04356618557030.339297556112-13.997430945-12.9459466284-24.6598795602
28.69078524408-2.640295866422.107911514857.81684871778-2.065580712427.733146650080.06048356071730.041283112478-0.2368516569260.0311475203092-0.0100111260697-0.4444002919850.1072130166990.03454369180280.05986746666590.2033195996880.01369776988790.0202063540330.2638191919630.007547323043080.261833368793.49017633416-25.0239049888-19.2138137179
34.00810323119-3.33201701007-1.196648568066.522658945353.723169629832.91622328810.121594245199-0.08468667275110.01752104091090.105908815971-0.1447487301910.409039153742-0.0924561329677-0.2460286212250.01249071127690.201726306413-0.0004724882000130.04337052128820.3230092103440.04550785484220.364278089489-14.0804657077-13.383931832-18.6478718322
43.507105552372.26477794318-4.720850461296.710292433030.3058526687749.434266110170.534501031781-0.2988319942991.25871352570.657144468136-0.1681338919520.837920109951-1.00399872839-0.248364441032-0.4030187780280.456286920180.01625477677680.06219651469770.295089287042-0.006713220508910.445015307302-5.355568633648.11179814478-17.8014957234
51.667057600430.321349415710.1252078571035.20288268656-1.564631860951.875097900090.110441974031-0.351740031064-0.03424607114210.468954055592-0.09643787155740.0704250594859-0.1739233227370.112968621639-0.01697612461420.24439362786-0.03432943586060.02910828765630.3573494289970.01966559748410.21841350583-1.37598918841-11.6820262466-13.3004417969
65.6699087469-3.10402023434-0.5986097795046.924143251231.894741874152.07398926401-0.00739071705836-0.7293216101310.1995796936010.6150513392870.0129559265204-0.6168709902920.2660161426650.780569290144-0.0641938238230.392581777209-0.0827877913537-0.01728762547950.5421969035450.04266436334640.38395045314512.4758869807-0.670562506802-18.7718792864
74.032198475692.3373235626-0.06156191046476.19055237972-0.7808514289811.24734794051-0.008756087595770.0603221434675-0.20174060649-0.02819522279710.00883310361614-0.324436983737-0.06354414710160.121005038584-0.003840905200410.199761946808-0.01672716323520.01227013357190.2893457192440.01917456926150.1478935848390.872698450158-11.2351137801-19.2301106335
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 952 through 975 )
2X-RAY DIFFRACTION2chain 'A' and (resid 976 through 991 )
3X-RAY DIFFRACTION3chain 'A' and (resid 992 through 1002 )
4X-RAY DIFFRACTION4chain 'A' and (resid 1003 through 1019 )
5X-RAY DIFFRACTION5chain 'A' and (resid 1020 through 1102 )
6X-RAY DIFFRACTION6(chain 'A' and (resid 1103 through 1113 )) or (chain 'B' and (resid 1116 through 1123 ))
7X-RAY DIFFRACTION7chain 'B' and (resid 1124 through 1161 )

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