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- PDB-7b64: Structure of NUDT15 V18I Mutant in complex with TH7755 -

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Basic information

Entry
Database: PDB / ID: 7b64
TitleStructure of NUDT15 V18I 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 / regulation of proteasomal protein catabolic process / xenobiotic 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: 1.5 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 1.1Mar 31, 2021Group: Database references / Category: citation / citation_author / Item: _citation.page_first / _citation.pdbx_database_id_DOI
Revision 1.2Apr 7, 2021Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jul 21, 2021Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.4Jan 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: Nucleotide triphosphate diphosphatase NUDT15
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,1042
Polymers18,6491
Non-polymers4541
Water1,910106
1
A: Nucleotide triphosphate diphosphatase NUDT15
hetero molecules

A: Nucleotide triphosphate diphosphatase NUDT15
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2074
Polymers37,2982
Non-polymers9092
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_656-x+1,y,-z+11
Buried area3190 Å2
ΔGint-19 kcal/mol
Surface area13620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.538, 34.624, 75.170
Angle α, β, γ (deg.)90.000, 148.548, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-327-

HOH

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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: 18649.029 Da / Num. of mol.: 1 / Mutation: V18I
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.: 1 / Source method: obtained synthetically / Formula: C22H22N4O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 106 / 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: 2.1 Å3/Da / Density % sol: 41.52 %
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, 20% PEG 500 MME, 20% PEG 2000

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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: 1.5→39.22 Å / Num. obs: 25129 / % possible obs: 100 % / Redundancy: 6.6 % / CC1/2: 0.994 / Net I/σ(I): 8.6
Reflection shellResolution: 1.5→1.53 Å / Num. unique obs: 1235 / CC1/2: 0.949

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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: 1.5→39.22 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.963 / SU B: 2.667 / SU ML: 0.087 / Cross valid method: FREE R-VALUE / ESU R: 0.076 / ESU R Free: 0.078
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2127 1247 4.963 %
Rwork0.1803 23878 -
all0.182 --
obs-25125 99.96 %
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: 39.688 Å2
Baniso -1Baniso -2Baniso -3
1--1.893 Å20 Å20.333 Å2
2---4.985 Å2-0 Å2
3---0.912 Å2
Refinement stepCycle: LAST / Resolution: 1.5→39.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1248 0 32 106 1386
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0131326
X-RAY DIFFRACTIONr_bond_other_d0.0010.0181169
X-RAY DIFFRACTIONr_angle_refined_deg1.7391.6611806
X-RAY DIFFRACTIONr_angle_other_deg1.4061.5922726
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9765156
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.11723.23971
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.84515213
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.414156
X-RAY DIFFRACTIONr_chiral_restr0.0820.2149
X-RAY DIFFRACTIONr_gen_planes_refined0.010.021480
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02283
X-RAY DIFFRACTIONr_nbd_refined0.2110.2224
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1830.21078
X-RAY DIFFRACTIONr_nbtor_refined0.1730.2625
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0840.2590
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1910.282
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0630.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1750.220
X-RAY DIFFRACTIONr_nbd_other0.3010.262
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1070.215
X-RAY DIFFRACTIONr_mcbond_it3.0683.874621
X-RAY DIFFRACTIONr_mcbond_other3.0483.871620
X-RAY DIFFRACTIONr_mcangle_it4.1475.808775
X-RAY DIFFRACTIONr_mcangle_other4.1445.811776
X-RAY DIFFRACTIONr_scbond_it4.4094.395705
X-RAY DIFFRACTIONr_scbond_other4.4064.395706
X-RAY DIFFRACTIONr_scangle_it6.5096.3871030
X-RAY DIFFRACTIONr_scangle_other6.5056.3881031
X-RAY DIFFRACTIONr_lrange_it7.82145.4771505
X-RAY DIFFRACTIONr_lrange_other7.79345.0121485
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.5390.341730.3281754X-RAY DIFFRACTION100
1.539-1.5810.264920.3011707X-RAY DIFFRACTION99.9444
1.581-1.6270.307860.2831670X-RAY DIFFRACTION99.9431
1.627-1.6770.305870.2571623X-RAY DIFFRACTION100
1.677-1.7320.2461040.2311560X-RAY DIFFRACTION100
1.732-1.7930.284710.2131485X-RAY DIFFRACTION100
1.793-1.860.232730.1921454X-RAY DIFFRACTION100
1.86-1.9360.198690.1821431X-RAY DIFFRACTION100
1.936-2.0220.25620.1931355X-RAY DIFFRACTION100
2.022-2.1210.235600.1741289X-RAY DIFFRACTION100
2.121-2.2350.174680.1721245X-RAY DIFFRACTION100
2.235-2.3710.246620.1791169X-RAY DIFFRACTION100
2.371-2.5340.191660.1761087X-RAY DIFFRACTION100
2.534-2.7360.22610.1651025X-RAY DIFFRACTION100
2.736-2.9970.224420.171946X-RAY DIFFRACTION100
2.997-3.350.194430.159875X-RAY DIFFRACTION100
3.35-3.8650.208540.15742X-RAY DIFFRACTION100
3.865-4.7290.168370.138650X-RAY DIFFRACTION100
4.729-6.6650.153240.174514X-RAY DIFFRACTION100
6.665-39.250.198130.174297X-RAY DIFFRACTION97.4843

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