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- PDB-5c5p: CRYSTAL STRUCTURE OF HUMAN TANKYRASE-2 IN COMPLEX WITH A PYRANOPY... -

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Basic information

Entry
Database: PDB / ID: 5c5p
TitleCRYSTAL STRUCTURE OF HUMAN TANKYRASE-2 IN COMPLEX WITH A PYRANOPYRIDONE INHIBITOR
Components(Tankyrase-2) x 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / WNT-SIGNALLING / BETA-CATENIN / PARP-DOMAIN / ADP-RIBOSYLATION / AXIN / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


XAV939 stabilizes AXIN / positive regulation of telomere capping / NAD+ ADP-ribosyltransferase / protein auto-ADP-ribosylation / negative regulation of telomere maintenance via telomere lengthening / 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 / protein auto-ADP-ribosylation / negative regulation of telomere maintenance via telomere lengthening / 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 / 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 / cytoplasm / cytosol
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) / Special / 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-0E0 / Poly [ADP-ribose] polymerase tankyrase-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsLukacs, C.M. / Janson, C.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Fragment-Based Drug Design of Novel Pyranopyridones as Cell Active and Orally Bioavailable Tankyrase Inhibitors.
Authors: de Vicente, J. / Tivitmahaisoon, P. / Berry, P. / Bolin, D.R. / Carvajal, D. / He, W. / Huang, K.S. / Janson, C. / Liang, L. / Lukacs, C. / Petersen, A. / Qian, H. / Yi, L. / Zhuang, Y. / Hermann, J.C.
History
DepositionJun 21, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 7, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Derived calculations / Refinement description / Category: pdbx_struct_oper_list / software
Item: _pdbx_struct_oper_list.symmetry_operation / _software.name
Revision 1.3Sep 27, 2023Group: 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)55,69712
Polymers54,6364
Non-polymers1,0628
Water8,035446
1
A: Tankyrase-2
C: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,8496
Polymers27,3182
Non-polymers5314
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6320 Å2
ΔGint-67 kcal/mol
Surface area10280 Å2
MethodPISA
2
B: Tankyrase-2
D: Tankyrase-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,8496
Polymers27,3182
Non-polymers5314
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6410 Å2
ΔGint-70 kcal/mol
Surface area10360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.803, 98.471, 117.321
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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
Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Production host: Escherichia coli (E. coli) / 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
Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS2, PARP5B, TANK2, TNKL / Production host: Escherichia coli (E. coli) / References: UniProt: Q9H2K2, NAD+ ADP-ribosyltransferase

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Non-polymers , 4 types, 454 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-0E0 / (3R)-3-(1-hydroxy-2-methylpropan-2-yl)-1,3,4,5-tetrahydro-6H-pyrano[4,3-c]isoquinolin-6-one


Mass: 273.327 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H19NO3
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 446 / 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: 2.44 Å3/Da / Density % sol: 49.69 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 30-40% PEG 3350, 5% SATURATED AMMONIUM SULFATE, 0.1M TRIS PH 8.5
PH range: 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Oct 15, 2010
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.75→45 Å / Num. obs: 53201 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 6.9 % / Biso Wilson estimate: 23.8 Å2 / Rmerge(I) obs: 0.045 / Net I/σ(I): 22.7
Reflection shellResolution: 1.75→1.84 Å / Redundancy: 6.7 % / Rmerge(I) obs: 0.445 / Mean I/σ(I) obs: 4 / % possible all: 99.9

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Processing

Software
NameVersionClassification
CNX2005refinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3KR8

3kr8


Resolution: 1.75→45 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 2154217.28 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.202 2635 5 %RANDOM
Rwork0.18 ---
obs0.181 53201 99.8 %-
all-53201 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 58.91 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso mean: 27.9 Å2
Baniso -1Baniso -2Baniso -3
1--1.32 Å20 Å20 Å2
2---3.66 Å20 Å2
3---4.99 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.21 Å0.18 Å
Luzzati d res low-5 Å
Luzzati sigma a0.18 Å0.16 Å
Refinement stepCycle: LAST / Resolution: 1.75→45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3333 0 62 455 3850
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.381
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d20.7
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.85
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.361.5
X-RAY DIFFRACTIONc_mcangle_it2.072
X-RAY DIFFRACTIONc_scbond_it2.052
X-RAY DIFFRACTIONc_scangle_it3.162.5
LS refinement shellResolution: 1.75→1.86 Å / Rfactor Rfree error: 0.014 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.295 448 5.1 %
Rwork0.267 8344 -
obs--100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAPROTEIN.TOP
X-RAY DIFFRACTION2LIG.PARLIG.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP
X-RAY DIFFRACTION5&_1_PARAMETER_INFILE_5&_1_TOPOLOGY_INFILE_5

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