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- PDB-7b67: Structure of NUDT15 V18_V19insGV Mutant in complex with TH7755 -

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Basic information

Entry
Database: PDB / ID: 7b67
TitleStructure of NUDT15 V18_V19insGV 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
PHOSPHATE ION / Chem-SYW / Nucleotide triphosphate diphosphatase NUDT15
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 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
B: Nucleotide triphosphate diphosphatase NUDT15
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,6116
Polymers37,5822
Non-polymers1,0284
Water7,278404
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
  • dimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3360 Å2
ΔGint-37 kcal/mol
Surface area14110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.431, 45.710, 66.339
Angle α, β, γ (deg.)90.000, 115.103, 90.000
Int Tables number4
Space group name H-MP1211

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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: 18791.186 Da / Num. of mol.: 2 / Mutation: V18_V19insGV
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-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 18.015 Da / Num. of mol.: 404 / 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: 2.45 Å3/Da / Density % sol: 49.77 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: 0.09 M SPG pH 5.0, 22.25% PEG 1500, 0.01 M sodium phosphate, 2.75% 1,2 propandiol, 1.0% glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96852 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96852 Å / Relative weight: 1
ReflectionResolution: 1.45→60.073 Å / Num. obs: 61265 / % possible obs: 100 % / Redundancy: 31.5 % / CC1/2: 1 / Net I/σ(I): 24.7
Reflection shellResolution: 1.45→1.47 Å / Num. unique obs: 3026 / CC1/2: 0.861

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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: 1.45→60.073 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.961 / SU B: 1.258 / SU ML: 0.047 / Cross valid method: FREE R-VALUE / ESU R: 0.063 / ESU R Free: 0.066
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1973 1996 3.268 %
Rwork0.1671 59087 -
all0.168 --
obs-61083 99.732 %
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: 20.958 Å2
Baniso -1Baniso -2Baniso -3
1--1.357 Å2-0 Å2-0.433 Å2
2--1.173 Å2-0 Å2
3---0.409 Å2
Refinement stepCycle: LAST / Resolution: 1.45→60.073 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2510 0 70 404 2984
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0132753
X-RAY DIFFRACTIONr_bond_other_d0.0010.0182408
X-RAY DIFFRACTIONr_angle_refined_deg1.8631.663768
X-RAY DIFFRACTIONr_angle_other_deg1.4721.595630
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4225335
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.4123.63146
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.66615437
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.0441511
X-RAY DIFFRACTIONr_chiral_restr0.0890.2309
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.023121
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02582
X-RAY DIFFRACTIONr_nbd_refined0.2460.2511
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1890.22311
X-RAY DIFFRACTIONr_nbtor_refined0.1750.21302
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0940.21156
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2060.2282
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2440.214
X-RAY DIFFRACTIONr_nbd_other0.2760.245
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1860.223
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.2150.21
X-RAY DIFFRACTIONr_mcbond_it1.8811.8851295
X-RAY DIFFRACTIONr_mcbond_other1.8811.8841293
X-RAY DIFFRACTIONr_mcangle_it2.7142.8241627
X-RAY DIFFRACTIONr_mcangle_other2.7142.8241628
X-RAY DIFFRACTIONr_scbond_it2.9262.2511458
X-RAY DIFFRACTIONr_scbond_other2.9252.2511459
X-RAY DIFFRACTIONr_scangle_it4.5923.2332135
X-RAY DIFFRACTIONr_scangle_other4.5913.2332136
X-RAY DIFFRACTIONr_lrange_it6.38923.9383280
X-RAY DIFFRACTIONr_lrange_other6.15422.733160
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
1.45-1.4880.2921470.26343260.26444840.8480.85799.75470.232
1.488-1.5280.2931580.2442150.24243910.8320.87499.59010.207
1.528-1.5730.2061400.21341230.21242830.9090.90299.5330.181
1.573-1.6210.2211440.19539740.19641310.9220.92899.68530.167
1.621-1.6740.2261250.18538900.18740230.920.93799.80110.16
1.674-1.7330.221430.18737370.18838920.9360.93899.69170.161
1.733-1.7980.2191370.17636060.17837500.9370.94599.81330.155
1.798-1.8720.1791420.17734600.17736060.9430.94299.88910.156
1.872-1.9550.2351350.21333140.21434890.9270.93498.85350.189
1.955-2.050.2021030.16932220.1733260.9490.95699.96990.153
2.05-2.1610.158660.15430710.15431380.9680.96699.96810.143
2.161-2.2920.202690.17729210.17830180.940.95899.07220.163
2.292-2.450.1941020.15827160.1628180.950.9591000.148
2.45-2.6460.165810.15325420.15426240.9620.96499.96190.144
2.646-2.8980.179800.15523450.15624250.9520.9631000.149
2.898-3.2390.222640.15921240.16121880.9480.9641000.158
3.239-3.7380.168730.14818830.14919560.9710.9741000.15
3.738-4.5730.171510.12716090.12816600.9730.9821000.132
4.573-6.4490.2200.15412800.15413000.9750.9781000.16
6.449-60.0730.214160.2027290.2037450.9460.9511000.204

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