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- PDB-7b65: Structure of NUDT15 R139C Mutant in complex with TH7755 -

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Basic information

Entry
Database: PDB / ID: 7b65
TitleStructure of NUDT15 R139C Mutant in complex with TH7755
ComponentsNucleotide triphosphate 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 / DNA protection ...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 / DNA protection / Phosphate bond hydrolysis by NUDT proteins / Azathioprine ADME / xenobiotic catabolic process / regulation of proteasomal protein catabolic process / response to reactive oxygen species / mitotic cell cycle / metal ion binding / cytosol
Similarity search - Function
NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily
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

Downloads & links

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Assembly

Deposited unit
A: Nucleotide triphosphate diphosphatase NUDT15
B: Nucleotide triphosphate diphosphatase NUDT15
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0714
Polymers37,1622
Non-polymers9092
Water3,837213
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
  • dimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3060 Å2
ΔGint-18 kcal/mol
Surface area13370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)34.910, 43.803, 60.457
Angle α, β, γ (deg.)91.582, 106.740, 113.478
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Nucleotide triphosphate diphosphatase NUDT15 / MutT homolog 2 / MTH2 / Nucleoside diphosphate-linked moiety X motif 15 / Nudix motif 15 / ...MutT homolog 2 / MTH2 / Nucleoside diphosphate-linked moiety X motif 15 / Nudix motif 15 / Nucleoside diphosphate-linked to another moiety X hydrolase 15 / Nudix hydrolase 15


Mass: 18580.951 Da / Num. of mol.: 2 / Mutation: R139C
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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 213 / 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: 2.16 Å3/Da / Density % sol: 42.95 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: 0.12 M Monosaccharide mix (Morpheus Screen) 0.1 M Imidazole/MES pH 6,5, 12.5% MPD, 12.5% PEG 1000, 12.5 % PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.97622 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 21, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97622 Å / Relative weight: 1
ReflectionResolution: 1.6→35.37 Å / Num. obs: 39574 / % possible obs: 96.6 % / Redundancy: 3.6 % / CC1/2: 0.997 / Net I/σ(I): 16.2
Reflection shellResolution: 1.6→1.63 Å / Num. unique obs: 1931 / CC1/2: 0.985

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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→35.37 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.963 / SU B: 1.542 / SU ML: 0.055 / Cross valid method: FREE R-VALUE / ESU R: 0.086 / ESU R Free: 0.083
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1843 1981 5.006 %
Rwork0.1597 37592 -
all0.161 --
obs-39573 96.595 %
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: 21.914 Å2
Baniso -1Baniso -2Baniso -3
1-0.797 Å20.265 Å2-0.433 Å2
2--0.964 Å2-0.403 Å2
3----1.346 Å2
Refinement stepCycle: LAST / Resolution: 1.6→35.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2472 0 64 213 2749
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0132685
X-RAY DIFFRACTIONr_bond_other_d0.0010.0182351
X-RAY DIFFRACTIONr_angle_refined_deg1.8861.6583674
X-RAY DIFFRACTIONr_angle_other_deg1.4971.595496
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1115322
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.61524.118136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.00215426
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.987158
X-RAY DIFFRACTIONr_chiral_restr0.0880.2304
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.023044
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02558
X-RAY DIFFRACTIONr_nbd_refined0.2260.2470
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1860.22191
X-RAY DIFFRACTIONr_nbtor_refined0.1750.21286
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.21236
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2090.2164
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0720.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2070.29
X-RAY DIFFRACTIONr_nbd_other0.1990.227
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.120.218
X-RAY DIFFRACTIONr_mcbond_it2.1272.0241270
X-RAY DIFFRACTIONr_mcbond_other2.1232.0211269
X-RAY DIFFRACTIONr_mcangle_it3.0233.0371598
X-RAY DIFFRACTIONr_mcangle_other3.0233.041599
X-RAY DIFFRACTIONr_scbond_it3.4052.4571415
X-RAY DIFFRACTIONr_scbond_other3.4042.4581416
X-RAY DIFFRACTIONr_scangle_it5.1963.5272076
X-RAY DIFFRACTIONr_scangle_other5.1943.5282077
X-RAY DIFFRACTIONr_lrange_it6.50625.2683071
X-RAY DIFFRACTIONr_lrange_other6.39724.7813020
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.6420.2341470.1882702X-RAY DIFFRACTION94.9667
1.642-1.6860.2331440.1872737X-RAY DIFFRACTION95.5873
1.686-1.7350.2461470.1762590X-RAY DIFFRACTION95.7663
1.735-1.7890.2181130.1772526X-RAY DIFFRACTION95.9636
1.789-1.8470.2121340.1682505X-RAY DIFFRACTION96.3139
1.847-1.9120.199860.1572415X-RAY DIFFRACTION96.4892
1.912-1.9840.198950.1642339X-RAY DIFFRACTION96.5107
1.984-2.0650.2311120.1622249X-RAY DIFFRACTION96.961
2.065-2.1570.221230.1622148X-RAY DIFFRACTION97.2591
2.157-2.2620.1881000.1652038X-RAY DIFFRACTION97.4476
2.262-2.3840.2141040.1651980X-RAY DIFFRACTION97.5199
2.384-2.5280.1681230.1551861X-RAY DIFFRACTION98.1692
2.528-2.7030.1761130.1541735X-RAY DIFFRACTION98.1934
2.703-2.9190.169950.1581632X-RAY DIFFRACTION98.2366
2.919-3.1960.172940.1551478X-RAY DIFFRACTION98.7437
3.196-3.5720.158820.1451353X-RAY DIFFRACTION98.8973
3.572-4.1220.139560.1371194X-RAY DIFFRACTION98.2704
4.122-5.0420.153590.1471007X-RAY DIFFRACTION95.6912
5.042-7.1030.171350.185774X-RAY DIFFRACTION97.0024
7.103-35.370.341190.218329X-RAY DIFFRACTION74.6781

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