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- PDB-7aom: Structure of NUDT15 in complex with Ganciclovir triphosphate -

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Basic information

Entry
Database: PDB / ID: 7aom
TitleStructure of NUDT15 in complex with Ganciclovir triphosphate
ComponentsNucleotide triphosphate diphosphatase NUDT15
KeywordsHYDROLASE / NUDIX hydrolase / antiviral
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 / xenobiotic catabolic process / regulation of proteasomal protein 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
Ganciclovir triphosphate / Nucleotide triphosphate diphosphatase NUDT15
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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

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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)38,3096
Polymers37,2702
Non-polymers1,0394
Water3,873215
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3310 Å2
ΔGint-35 kcal/mol
Surface area13270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.243, 49.532, 135.032
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 11 through 75 or resid 77 through 164 or resid 201))
d_2ens_1(chain "B" and (resid 11 through 75 or resid 77 through 164 or resid 201))

NCS domain segments:

Ens-ID: ens_1

Dom-IDComponent-IDBeg label comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ARGVALAA11 - 751 - 65
d_12PHELEUAA77 - 16468 - 155
d_13GCTGCTAB201
d_21ARGVALBC11 - 751 - 65
d_22PHELEUBC77 - 16468 - 155
d_23GCTGCTBD201

NCS oper: (Code: givenMatrix: (0.14557614524, -0.978208803023, -0.148037575045), (-0.974952818709, -0.167274594542, 0.146581756407), (-0.168150489823, 0.122990844005, -0.978058620464)Vector: -31. ...NCS oper: (Code: given
Matrix: (0.14557614524, -0.978208803023, -0.148037575045), (-0.974952818709, -0.167274594542, 0.146581756407), (-0.168150489823, 0.122990844005, -0.978058620464)
Vector: -31.7293655951, -42.3354230028, 31.9785529047)

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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.: 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-RQ2 / Ganciclovir triphosphate / [[(2~{R})-2-[(2-azanyl-6-oxidanylidene-1~{H}-purin-9-yl)methoxy]-3-oxidanyl-propoxy]-oxidanyl-phosphoryl] phosphono hydrogen phosphate


Mass: 495.170 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 215 / 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: 2.07 Å3/Da / Density % sol: 40.71 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1M Tris pH 8.5, 0.2M sodium acetate, 34% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 16, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→46.5 Å / Num. obs: 23223 / % possible obs: 99.49 % / Redundancy: 12.8 % / Biso Wilson estimate: 25.53 Å2 / CC1/2: 0.972 / CC star: 0.993 / Rmerge(I) obs: 0.1735 / Rrim(I) all: 0.1812 / Net I/av σ(I): 7.66 / Net I/σ(I): 7.66
Reflection shellResolution: 1.95→2.022 Å / Redundancy: 13.6 % / Rmerge(I) obs: 0.7252 / Mean I/σ(I) obs: 0.75 / Num. unique obs: 2217 / CC1/2: 0.873 / CC star: 0.966 / Rrim(I) all: 0.7554 / % possible all: 96.89

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
DIALS3.0.0data reduction
DIALS3.0.0data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LPG

5lpg


Resolution: 1.95→46.5 Å / SU ML: 0.2214 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.3155
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2234 1208 5.21 %
Rwork0.2036 21986 -
obs0.2047 23194 99.49 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.5 Å2
Refinement stepCycle: LAST / Resolution: 1.95→46.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2482 0 62 215 2759
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01642644
X-RAY DIFFRACTIONf_angle_d1.0883604
X-RAY DIFFRACTIONf_chiral_restr0.0975358
X-RAY DIFFRACTIONf_plane_restr0.0056462
X-RAY DIFFRACTIONf_dihedral_angle_d15.0545950
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 0.697906181428 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-2.030.32451270.26742325X-RAY DIFFRACTION97.15
2.03-2.120.26561390.24752409X-RAY DIFFRACTION99.77
2.12-2.230.25591340.24272416X-RAY DIFFRACTION99.8
2.23-2.370.24551310.23432417X-RAY DIFFRACTION100
2.37-2.560.26031260.22262427X-RAY DIFFRACTION99.73
2.56-2.820.20351170.23892439X-RAY DIFFRACTION99.19
2.82-3.220.24351390.21912464X-RAY DIFFRACTION100
3.22-4.060.18471340.17342475X-RAY DIFFRACTION99.89
4.06-46.50.20531610.16662614X-RAY DIFFRACTION99.86
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)
12.533066493721.153630493030.8971907853111.403134514380.1285700165391.49160651787-0.05679973970940.140025317846-0.104916095184-0.09797762319360.0868971641316-0.252565227892-0.2117724544660.285872022675-0.004400665080280.1926114099610.02329421174210.03380069111440.1488646710250.003236244044960.199245294315-8.54178501388-11.593833488221.2624230565
21.292941161840.3661935047170.09693306843510.549275178225-0.01319354923660.484458596364-0.0868462691643-0.03119952313050.0545527740698-0.2732504239070.205078509846-0.221526092304-0.385859248660.3765509876840.0002781287569980.382207803283-0.04359423603190.06295195767880.254050652713-0.00678067764820.269314324842-3.80343907986-3.3238295889118.7819341856
30.7915165228470.3823206296970.3565986783532.331009715682.156170777632.478155995-0.271472078706-0.09013965451980.203565033257-0.4271309412450.2449403874290.203706468127-0.8595960738180.08186795644110.1563400520930.4293674718410.0886043855578-0.02323545394520.1552468052040.0263687955640.254942007189-20.4083931285-8.0109033681812.6849520496
40.9468086690931.054945333030.9272426744581.970210976971.855909694753.181270633590.158022546947-0.283418431691-0.273206315853-0.04509222259990.0640936855682-0.1784897361640.313580644067-0.8481768650620.04006205674470.1521763360870.00972115712667-0.02315156492780.2178139996340.0748953724520.226775654525-24.5462216947-28.941701978311.4992604115
51.09671467863-0.356447941540.01635425517351.50487796901-0.4047300336451.416260253790.692117375466-0.837547834989-0.194712777953-0.0817781392492-0.258260128670.2488511909590.831443753357-1.36891031620.3870338989670.325580411895-0.260656444882-0.1204794199990.6622776917150.1578561398810.296613424063-33.7547917627-35.85487393119.73507209955
62.345658507851.220278603722.326513820532.802623590552.803208588813.453041329560.484327375978-0.846481817157-0.04688032134240.616407546274-0.48939566610.2994223421050.242182474648-1.919587297850.4914883405340.06871873956560.08922404178140.0859913078780.6829163144160.04299396962320.230689934534-28.1219964402-23.045957410622.4043711601
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain A and resid 11:104)AA11 - 1041 - 95
22(chain A and resid 105:140)AA105 - 14096 - 131
33(chain A and resid 141:164)AA141 - 164132 - 155
44(chain B and resid 11:102)BC11 - 1021 - 93
55(chain B and resid 103:131)BC103 - 13194 - 122
66(chain B and resid 132:164)BC132 - 164123 - 155

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