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- PDB-4w6e: Human Tankyrase 1 with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 4w6e
TitleHuman Tankyrase 1 with small molecule inhibitor
ComponentsTankyrase-1
KeywordsTRANSFERASE/INHIBITOR / Tankyrase Inhibitor Small Molecule / TRANSFERASE-INHIBITOR complex
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 / : / NAD+-protein ADP-ribosyltransferase activity / positive regulation of telomere capping / NAD+-protein poly-ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / mRNA transport / spindle assembly / nuclear pore / positive regulation of telomere maintenance via telomerase / nucleotidyltransferase activity / mitotic spindle organization / TCF dependent signaling in response to WNT / peptidyl-threonine phosphorylation / Degradation of AXIN / 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 / Golgi membrane / cell division / 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 / 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 / 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-3J5 / Poly [ADP-ribose] polymerase tankyrase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsKazmirski, S.L. / Johannes, J. / Boriack-Sjodin, P.A. / Howard, T.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Pyrimidinone nicotinamide mimetics as selective tankyrase and wnt pathway inhibitors suitable for in vivo pharmacology.
Authors: Johannes, J.W. / Almeida, L. / Barlaam, B. / Boriack-Sjodin, P.A. / Casella, R. / Croft, R.A. / Dishington, A.P. / Gingipalli, L. / Gu, C. / Hawkins, J.L. / Holmes, J.L. / Howard, T. / ...Authors: Johannes, J.W. / Almeida, L. / Barlaam, B. / Boriack-Sjodin, P.A. / Casella, R. / Croft, R.A. / Dishington, A.P. / Gingipalli, L. / Gu, C. / Hawkins, J.L. / Holmes, J.L. / Howard, T. / Huang, J. / Ioannidis, S. / Kazmirski, S. / Lamb, M.L. / McGuire, T.M. / Moore, J.E. / Ogg, D. / Patel, A. / Pike, K.G. / Pontz, T. / Robb, G.R. / Su, N. / Wang, H. / Wu, X. / Zhang, H.J. / Zhang, Y. / Zheng, X. / Wang, T.
History
DepositionAug 20, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 13, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_oper_list / refine_hist / struct_keywords
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_nucleic_acid / _struct_keywords.text

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tankyrase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7483
Polymers24,2281
Non-polymers5212
Water4,071226
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)80.774, 81.847, 83.309
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number24
Space group name H-MI212121

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Components

#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: 24227.508 Da / Num. of mol.: 1 / Fragment: PARP DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNKS, PARP5A, PARPL, TIN1, TINF1, TNKS1 / Production host: Escherichia coli (E. coli) / References: UniProt: O95271, NAD+ ADP-ribosyltransferase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-3J5 / 2-(4-{6-[(3S)-3,4-dimethylpiperazin-1-yl]-4-methylpyridin-3-yl}phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one


Mass: 455.551 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H29N5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 226 / 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: 2.86 Å3/Da / Density % sol: 56.92 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 1.4 Sodium Formate, 0.1 Sodium Acetate pH 5

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Apr 20, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.95→58.38 Å / Num. obs: 20488 / % possible obs: 100 % / Redundancy: 6.82 % / Biso Wilson estimate: 36.93 Å2 / Rsym value: 0.068 / Net I/σ(I): 11.2
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 5.31 % / Rmerge(I) obs: 0.467 / Mean I/σ(I) obs: 2.4 / % possible all: 100

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Processing

SoftwareName: BUSTER / Version: 2.11.5 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→40.39 Å / Cor.coef. Fo:Fc: 0.9482 / Cor.coef. Fo:Fc free: 0.9128 / SU R Cruickshank DPI: 0.156 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.17 / SU Rfree Blow DPI: 0.159 / SU Rfree Cruickshank DPI: 0.153
RfactorNum. reflection% reflectionSelection details
Rfree0.2541 1044 5.11 %RANDOM
Rwork0.2047 ---
obs0.2071 20430 99.71 %-
Displacement parametersBiso mean: 40.85 Å2
Baniso -1Baniso -2Baniso -3
1-6.0787 Å20 Å20 Å2
2---0.0817 Å20 Å2
3----5.997 Å2
Refine analyzeLuzzati coordinate error obs: 0.262 Å
Refinement stepCycle: 1 / Resolution: 1.95→40.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1689 0 35 226 1950
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0091769HARMONIC2
X-RAY DIFFRACTIONt_angle_deg12381HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d619SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes40HARMONIC2
X-RAY DIFFRACTIONt_gen_planes261HARMONIC5
X-RAY DIFFRACTIONt_it1769HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.79
X-RAY DIFFRACTIONt_other_torsion16.71
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion215SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2132SEMIHARMONIC4
LS refinement shellResolution: 1.95→2.06 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2185 149 5.09 %
Rwork0.2058 2777 -
all0.2065 2926 -
obs--99.71 %
Refinement TLS params.Method: refined / Origin x: 17.4764 Å / Origin y: 14.0783 Å / Origin z: -19.37 Å
111213212223313233
T-0.0867 Å2-0.0107 Å20.0059 Å2--0.0701 Å2-0.0024 Å2---0.0427 Å2
L2.1592 °20.1495 °20.6585 °2-0.9717 °2-0.0594 °2--1.1953 °2
S-0.0964 Å °0.1835 Å °0.046 Å °0.0527 Å °0.0358 Å °0.0579 Å °-0.0263 Å °0.1824 Å °0.0606 Å °
Refinement TLS groupSelection details: { A|* }

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