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- PDB-7aop: Structure of NUDT15 in complex with inhibitor TH8321 -

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Basic information

Entry
Database: PDB / ID: 7aop
TitleStructure of NUDT15 in complex with inhibitor TH8321
ComponentsNucleotide triphosphate diphosphatase NUDT15
KeywordsHYDROLASE / NUDIX hydrolase / inhibitor
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-RTW / Nucleotide triphosphate diphosphatase NUDT15
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsRehling, D. / Zhang, S.M. / Helleday, T. / Stenmark, P.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Swedish Research Council Sweden
CitationJournal: Cell Chem Biol / Year: 2021
Title: NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir.
Authors: Zhang, S.M. / Rehling, D. / Jemth, A.S. / Throup, A. / Landazuri, N. / Almlof, I. / Gottmann, M. / Valerie, N.C.K. / Borhade, S.R. / Wakchaure, P. / Page, B.D.G. / Desroses, M. / Homan, E.J. ...Authors: Zhang, S.M. / Rehling, D. / Jemth, A.S. / Throup, A. / Landazuri, N. / Almlof, I. / Gottmann, M. / Valerie, N.C.K. / Borhade, S.R. / Wakchaure, P. / Page, B.D.G. / Desroses, M. / Homan, E.J. / Scobie, M. / Rudd, S.G. / Berglund, U.W. / Soderberg-Naucler, C. / Stenmark, P. / Helleday, T.
History
DepositionOct 14, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 2, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Dec 29, 2021Group: Database references / Category: citation / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Dec 21, 2022Group: Database references / Source and taxonomy / Structure summary
Category: citation / entity ...citation / entity / entity_name_com / entity_src_gen
Item: _citation.page_last / _entity.pdbx_description ..._citation.page_last / _entity.pdbx_description / _entity_name_com.name / _entity_src_gen.gene_src_common_name
Revision 1.4Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nucleotide triphosphate diphosphatase NUDT15
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0153
Polymers18,6351
Non-polymers3802
Water1,02757
1
A: Nucleotide triphosphate diphosphatase NUDT15
hetero molecules

A: Nucleotide triphosphate diphosphatase NUDT15
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0306
Polymers37,2702
Non-polymers7604
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area3430 Å2
ΔGint-36 kcal/mol
Surface area13730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.602, 48.602, 134.399
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Space group name HallP4nw2abw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+3/4
#3: y+1/2,-x+1/2,z+1/4
#4: x+1/2,-y+1/2,-z+1/4
#5: -x+1/2,y+1/2,-z+3/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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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: 18635.002 Da / Num. of mol.: 1
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-RTW / 2-azanyl-9-cyclohexyl-8-(2-methoxyphenyl)-3~{H}-purine-6-thione / TH8321


Mass: 355.457 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21N5OS / 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.: 57 / 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: 2.13 Å3/Da / Density % sol: 42.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Tris pH 8.0, 0.2 M sodium acetate, 29.5% 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: 0.7749 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: 0.7749 Å / Relative weight: 1
ReflectionResolution: 2.35→45.71 Å / Num. obs: 7239 / % possible obs: 99.48 % / Redundancy: 15.9 % / Biso Wilson estimate: 39.67 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.2083 / Rrim(I) all: 0.2152 / Net I/σ(I): 11.05
Reflection shellResolution: 2.35→2.437 Å / Redundancy: 16.4 % / Rmerge(I) obs: 1.168 / Mean I/σ(I) obs: 1.64 / Num. unique obs: 713 / CC1/2: 0.798 / CC star: 0.942 / Rrim(I) all: 1.206 / % possible all: 99.03

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
DIALS3.1.0data reduction
DIALS3.1.0data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LPG

5lpg


Resolution: 2.35→45.71 Å / SU ML: 0.2214 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.733
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2369 700 9.72 %
Rwork0.1964 6501 -
obs0.2003 7201 99.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 43.87 Å2
Refinement stepCycle: LAST / Resolution: 2.35→45.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1247 0 26 57 1330
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00791325
X-RAY DIFFRACTIONf_angle_d1.30671803
X-RAY DIFFRACTIONf_chiral_restr0.0786179
X-RAY DIFFRACTIONf_plane_restr0.0042234
X-RAY DIFFRACTIONf_dihedral_angle_d14.1186477
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.35-2.530.26141440.25441240X-RAY DIFFRACTION98.86
2.53-2.790.28861280.24241263X-RAY DIFFRACTION99.14
2.79-3.190.29981560.22791270X-RAY DIFFRACTION99.65
3.19-4.020.2561250.19051322X-RAY DIFFRACTION99.79
4.02-45.710.17981470.16481406X-RAY DIFFRACTION99.87
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.88193015299-1.631844286470.3286476777241.26433968394-1.052213612363.455617019840.0423047898372-0.469311023246-0.596508720332-0.1241057993130.0981900298690.2769120755970.332538214980.0652344637420.01341909708820.286608212235-0.035780201027-0.05623281774760.2752601209950.04334522429150.34462392857913.2317394341-3.97277339866.98801940508
23.64099255906-1.20083324540.01519047262291.86860312545-0.6237090317422.432720150040.0475074674038-0.228903471588-0.477804109679-0.3462983847830.04867091506460.1226858216640.4336927831820.2186106701540.0007991952801930.4085548739870.0316091629853-0.05255678195990.2679439883830.02659808512630.3539434952917.1216036971-7.509512593922.71747108911
32.05662182848-1.67675319732-0.05388701795712.27195183836-1.150453505611.552605837580.2232178689710.269031433320.0924133277189-0.239402464277-0.25620140622-0.1500986628460.1850286832330.2736255543527.04143630959E-70.352396844031-0.0189426548597-0.004572852453170.380364800813-0.01289188102840.36460511648616.43423989245.86375011978-4.7987439321
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11(chain A and resid 9:83)9 - 831 - 76
22(chain A and resid 84:138)84 - 13877 - 131
33(chain A and resid 139:164)139 - 164132 - 157

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