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- PDB-7b63: Structure of NUDT15 in complex with TH7755 -

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Basic information

Entry
Database: PDB / ID: 7b63
TitleStructure of NUDT15 in complex with TH7755
ComponentsProbable 8-oxo-dGTP diphosphatase NUDT15
KeywordsHYDROLASE / Inhibitor / complex / Nucleoside Triphosphate Pyrophosphohydrolase
Function / homology
Function and homology information


nucleoside phosphate catabolic process / purine nucleotide catabolic process / nucleotide diphosphatase / nucleobase-containing small molecule metabolic process / nucleoside triphosphate diphosphatase activity / 8-oxo-dGDP phosphatase activity / dGTP catabolic process / 8-oxo-7,8-dihydrodeoxyguanosine triphosphate pyrophosphatase activity / 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity / Phosphate bond hydrolysis by NUDT proteins ...nucleoside phosphate catabolic process / purine nucleotide catabolic process / nucleotide diphosphatase / nucleobase-containing small molecule metabolic process / nucleoside triphosphate diphosphatase activity / 8-oxo-dGDP phosphatase activity / dGTP catabolic process / 8-oxo-7,8-dihydrodeoxyguanosine triphosphate pyrophosphatase activity / 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity / Phosphate bond hydrolysis by NUDT proteins / DNA protection / Azathioprine ADME / regulation of proteasomal protein catabolic process / xenobiotic catabolic process / response to reactive oxygen species / mitotic cell cycle / metal ion binding / cytosol
Similarity search - Function
Nucleoside Triphosphate Pyrophosphohydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-SYW / Nucleotide triphosphate diphosphatase NUDT15
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsRehling, D. / Stenmark, P.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Swedish Research Council2018-03406 Sweden
CitationJournal: J.Biol.Chem. / Year: 2021
Title: Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity.
Authors: Rehling, D. / Zhang, S.M. / Jemth, A.S. / Koolmeister, T. / Throup, A. / Wallner, O. / Scaletti, E. / Moriyama, T. / Nishii, R. / Davies, J. / Desroses, M. / Rudd, S.G. / Scobie, M. / Homan, ...Authors: Rehling, D. / Zhang, S.M. / Jemth, A.S. / Koolmeister, T. / Throup, A. / Wallner, O. / Scaletti, E. / Moriyama, T. / Nishii, R. / Davies, J. / Desroses, M. / Rudd, S.G. / Scobie, M. / Homan, E. / Berglund, U.W. / Yang, J.J. / Helleday, T. / Stenmark, P.
History
DepositionDec 7, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 24, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 21, 2021Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Jan 31, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Probable 8-oxo-dGTP diphosphatase NUDT15
B: Probable 8-oxo-dGTP diphosphatase NUDT15
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2035
Polymers37,2702
Non-polymers9333
Water6,269348
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
  • dimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3340 Å2
ΔGint-26 kcal/mol
Surface area14150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.602, 45.641, 67.023
Angle α, β, γ (deg.)90.000, 115.998, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Probable 8-oxo-dGTP diphosphatase NUDT15 / 8-oxo-dGTPase NUDT15 / 7 / 8-dihydro-8-oxoguanine-triphosphatase NUDT15 / MutT homolog 2 / MTH2 / ...8-oxo-dGTPase NUDT15 / 7 / 8-dihydro-8-oxoguanine-triphosphatase NUDT15 / MutT homolog 2 / MTH2 / Nucleoside diphosphate-linked moiety X motif 15 / Nudix motif 15


Mass: 18635.002 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NUDT15, MTH2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q9NV35, nucleotide diphosphatase
#2: Chemical ChemComp-SYW / (R)-6-((2-methyl-4-(1-methyl-1H-indole-5-carbonyl)piperazin-1-yl)sulfonyl)benzo[d]oxazol-2(3H)-one / 6-[(2~{R})-2-methyl-4-(1-methylindol-5-yl)carbonyl-piperazin-1-yl]sulfonyl-3~{H}-1,3-benzoxazol-2-one / TH7755


Mass: 454.499 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H22N4O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 348 / Source method: isolated from a natural source / Formula: H2O
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: 2.35 Å3/Da / Density % sol: 47.57 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Tris pH 8.0, 0.2 M sodium acetate, 38% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.9184 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 20, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.6→60.24 Å / Num. obs: 45919 / % possible obs: 100 % / Redundancy: 6.8 % / CC1/2: 0.999 / Net I/σ(I): 15.1
Reflection shellResolution: 1.6→1.63 Å / Num. unique obs: 2312 / CC1/2: 0.862

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PHENIX1.18.2refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LPG

5lpg


Resolution: 1.6→60.24 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.962 / SU B: 1.688 / SU ML: 0.058 / Cross valid method: FREE R-VALUE / ESU R: 0.082 / ESU R Free: 0.083
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1962 2245 4.892 %
Rwork0.1669 43650 -
all0.168 --
obs-45895 99.963 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 24.514 Å2
Baniso -1Baniso -2Baniso -3
1--1.506 Å20 Å2-0.266 Å2
2--0.832 Å20 Å2
3---0.633 Å2
Refinement stepCycle: LAST / Resolution: 1.6→60.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2512 0 65 348 2925
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0132667
X-RAY DIFFRACTIONr_bond_other_d0.0010.0182354
X-RAY DIFFRACTIONr_angle_refined_deg1.8271.6623633
X-RAY DIFFRACTIONr_angle_other_deg1.4551.5925485
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4745312
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.51123.239142
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.71115427
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8331512
X-RAY DIFFRACTIONr_chiral_restr0.0910.2297
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.022990
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02568
X-RAY DIFFRACTIONr_nbd_refined0.2110.2445
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1770.22204
X-RAY DIFFRACTIONr_nbtor_refined0.1730.21242
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0830.21172
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1840.2255
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2380.26
X-RAY DIFFRACTIONr_nbd_other0.1830.227
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1910.211
X-RAY DIFFRACTIONr_mcbond_it2.242.261251
X-RAY DIFFRACTIONr_mcbond_other2.2392.2591250
X-RAY DIFFRACTIONr_mcangle_it3.223.3891562
X-RAY DIFFRACTIONr_mcangle_other3.2193.391563
X-RAY DIFFRACTIONr_scbond_it3.312.6731416
X-RAY DIFFRACTIONr_scbond_other3.3092.6731417
X-RAY DIFFRACTIONr_scangle_it5.1453.8312071
X-RAY DIFFRACTIONr_scangle_other5.1433.8322072
X-RAY DIFFRACTIONr_lrange_it6.88927.7073094
X-RAY DIFFRACTIONr_lrange_other6.64826.6152991
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.6-1.6420.2591620.26332270.26233950.8890.88799.82330.241
1.642-1.6860.2611770.24331290.24433080.9020.89699.93950.22
1.686-1.7350.2561610.21330090.21531720.9010.91799.9370.188
1.735-1.7890.2151500.20129460.20230960.9290.9291000.179
1.789-1.8470.2271340.18828850.18930190.9290.9351000.167
1.847-1.9120.1831220.16827940.16929160.950.9491000.152
1.912-1.9840.2311350.18326940.18528300.9350.94499.96470.166
1.984-2.0650.2331260.17325520.17526780.9360.9531000.161
2.065-2.1570.1891440.16424450.16525890.9540.9621000.155
2.157-2.2620.21180.16723850.16925030.9480.9561000.16
2.262-2.3840.2071330.16422350.16723680.9440.9541000.158
2.384-2.5290.1821110.14421470.14622580.960.9681000.139
2.529-2.7030.2291050.15819950.16121010.9480.9699.95240.155
2.703-2.9190.186890.15318730.15519630.9550.96699.94910.154
2.919-3.1970.193840.16217300.16418160.9570.96499.88990.164
3.197-3.5730.225570.16615930.16816500.9530.9621000.174
3.573-4.1230.171680.13914000.1414680.9650.9721000.149
4.123-5.0440.146770.14111640.14112410.9750.9791000.155
5.044-7.1080.186530.1779190.1789720.9750.9761000.188
7.108-60.240.164390.2055270.2025680.9730.96599.64790.214

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