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- PDB-4li6: TANKYRASE-1 Complexed with small molecule inhibitor N-[(4-oxo-3,4... -

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Basic information

Entry
Database: PDB / ID: 4li6
TitleTANKYRASE-1 Complexed with small molecule inhibitor N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-3-phenyl-N-(thiophen-2-ylmethyl)propanamide
ComponentsTankyrase-1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-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-1XO / Poly [ADP-ribose] polymerase tankyrase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER METHODS / Resolution: 2.05 Å
AuthorsKirby, C.A. / Stams, T.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Identification of NVP-TNKS656: The Use of Structure-Efficiency Relationships To Generate a Highly Potent, Selective, and Orally Active Tankyrase Inhibitor.
Authors: Shultz, M.D. / Cheung, A.K. / Kirby, C.A. / Firestone, B. / Fan, J. / Chen, C.H. / Chen, Z. / Chin, D.N. / Dipietro, L. / Fazal, A. / Feng, Y. / Fortin, P.D. / Gould, T. / Lagu, B. / Lei, H. ...Authors: Shultz, M.D. / Cheung, A.K. / Kirby, C.A. / Firestone, B. / Fan, J. / Chen, C.H. / Chen, Z. / Chin, D.N. / Dipietro, L. / Fazal, A. / Feng, Y. / Fortin, P.D. / Gould, T. / Lagu, B. / Lei, H. / Lenoir, F. / Majumdar, D. / Ochala, E. / Palermo, M.G. / Pham, L. / Pu, M. / Smith, T. / Stams, T. / Tomlinson, R.C. / Toure, B.B. / Visser, M. / Wang, R.M. / Waters, N.J. / Shao, W.
History
DepositionJul 2, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tankyrase-1
B: Tankyrase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,23811
Polymers50,8192
Non-polymers1,4189
Water6,251347
1
A: Tankyrase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,2637
Polymers25,4101
Non-polymers8536
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tankyrase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,9754
Polymers25,4101
Non-polymers5653
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)124.082, 44.814, 87.846
Angle α, β, γ (deg.)90.00, 90.22, 90.00
Int Tables number5
Space group name H-MC121

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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: 25409.711 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, UNP residues 1105-1325
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.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-1XO / N-[(4-oxo-3,4-dihydroquinazolin-2-yl)methyl]-3-phenyl-N-(thiophen-2-ylmethyl)propanamide


Mass: 403.497 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21N3O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 347 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsSEQUENCE CONFLICT M1266I PRESENT IN UNP ENTRY O95271

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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: 2.4 Å3/Da / Density % sol: 48.81 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.8
Details: EQUAL VOLUMES (2 UL) OF RESERVIOR SOLUTION AND PROTEIN SOLUTION WERE MIXED AND SET AS HANGING DROPS. 15% PEG3350, 100MM BIS-TRIS PH5.8, 310MM AMMONIUM SULFATE. PROTEIN SOLUTION: 20 MG/ML IN ...Details: EQUAL VOLUMES (2 UL) OF RESERVIOR SOLUTION AND PROTEIN SOLUTION WERE MIXED AND SET AS HANGING DROPS. 15% PEG3350, 100MM BIS-TRIS PH5.8, 310MM AMMONIUM SULFATE. PROTEIN SOLUTION: 20 MG/ML IN 25 MM TRIS PH8, 200MM NACL, 1MM TCEP, 1MM PJ34. CRYSTALS WERE THEN MOVED INTO A SOAKING SOLUTION CONTAINING 18% PEG 3350, 320MM AMMONIUM SULFATE, 100MM BIS-TRIS PH 5.8, 0.2 MM inhibitor, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Sep 24, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. obs: 30133 / % possible obs: 98 % / Rmerge(I) obs: 0.116
Reflection shellResolution: 2.05→2.12 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.379 / Mean I/σ(I) obs: 4.91 / % possible all: 96.1

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Processing

Software
NameVersionClassification
PHENIXmodel building
PHENIX(phenix.refine: 1.8_1069)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: FOURIER METHODS / Resolution: 2.05→26.52 Å / SU ML: 0.2 / σ(F): 1.33 / Phase error: 23.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2239 1989 6.62 %
Rwork0.1724 --
obs0.1758 30067 97.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.67 Å2
Baniso -1Baniso -2Baniso -3
1--2.2199 Å20 Å22.6828 Å2
2--11.2467 Å20 Å2
3----9.0268 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: LAST / Resolution: 2.05→26.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3332 0 85 347 3764
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073500
X-RAY DIFFRACTIONf_angle_d1.0734706
X-RAY DIFFRACTIONf_dihedral_angle_d13.6371338
X-RAY DIFFRACTIONf_chiral_restr0.072457
X-RAY DIFFRACTIONf_plane_restr0.005619
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.09970.30371320.20291922X-RAY DIFFRACTION95
2.0997-2.15640.24721430.18931980X-RAY DIFFRACTION97
2.1564-2.21980.25881400.19041957X-RAY DIFFRACTION97
2.2198-2.29140.28091400.18712003X-RAY DIFFRACTION98
2.2914-2.37330.23431360.18381951X-RAY DIFFRACTION96
2.3733-2.46820.271450.19092019X-RAY DIFFRACTION98
2.4682-2.58050.28531370.19521967X-RAY DIFFRACTION98
2.5805-2.71640.26331450.20342017X-RAY DIFFRACTION98
2.7164-2.88640.24791410.20162025X-RAY DIFFRACTION98
2.8864-3.1090.23911460.20422001X-RAY DIFFRACTION98
3.109-3.42120.20671420.15812046X-RAY DIFFRACTION99
3.4212-3.91490.19241490.14552039X-RAY DIFFRACTION99
3.9149-4.92720.19161430.13832056X-RAY DIFFRACTION98
4.9272-26.520.18871500.17312095X-RAY DIFFRACTION98

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