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- PDB-4n1t: Structure of human MTH1 in complex with TH287 -

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Basic information

Entry
Database: PDB / ID: 4n1t
TitleStructure of human MTH1 in complex with TH287
Components7,8-dihydro-8-oxoguanine triphosphatase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Oxidised nucleotide degradation / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


2-hydroxy-ATP hydrolase activity / 2-hydroxy-dATP hydrolase activity / N6-methyl-(d)ATP hydrolase activity / O6-methyl-dGTP hydrolase activity / 2-hydroxy-dATP diphosphatase / dATP diphosphatase activity / ATP diphosphatase activity / 8-oxo-7,8-dihydrodeoxyguanosine triphosphate pyrophosphatase activity / 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity / hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides ...2-hydroxy-ATP hydrolase activity / 2-hydroxy-dATP hydrolase activity / N6-methyl-(d)ATP hydrolase activity / O6-methyl-dGTP hydrolase activity / 2-hydroxy-dATP diphosphatase / dATP diphosphatase activity / ATP diphosphatase activity / 8-oxo-7,8-dihydrodeoxyguanosine triphosphate pyrophosphatase activity / 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity / hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides / DNA protection / Phosphate bond hydrolysis by NUDT proteins / purine nucleoside catabolic process / snoRNA binding / Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides / response to cadmium ion / acrosomal vesicle / male gonad development / nuclear membrane / response to oxidative stress / mitochondrial matrix / DNA repair / mitochondrion / extracellular space / nucleus / metal ion binding / cytosol / cytoplasm
Similarity search - Function
Oxidized purine nucleoside triphosphate / NUDIX hydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / NUDIX hydrolase, conserved site / Nudix box signature. / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily ...Oxidized purine nucleoside triphosphate / NUDIX hydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / NUDIX hydrolase, conserved site / Nudix box signature. / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-2GD / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsBerntsson, R.P.-A. / Jemth, A. / Gustafsson, R. / Svensson, L.M. / Helleday, T. / Stenmark, P.
CitationJournal: Nature / Year: 2014
Title: MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.
Authors: Gad, H. / Koolmeister, T. / Jemth, A.S. / Eshtad, S. / Jacques, S.A. / Strom, C.E. / Svensson, L.M. / Schultz, N. / Lundback, T. / Einarsdottir, B.O. / Saleh, A. / Gokturk, C. / ...Authors: Gad, H. / Koolmeister, T. / Jemth, A.S. / Eshtad, S. / Jacques, S.A. / Strom, C.E. / Svensson, L.M. / Schultz, N. / Lundback, T. / Einarsdottir, B.O. / Saleh, A. / Gokturk, C. / Baranczewski, P. / Svensson, R. / Berntsson, R.P. / Gustafsson, R. / Stromberg, K. / Sanjiv, K. / Jacques-Cordonnier, M.C. / Desroses, M. / Gustavsson, A.L. / Olofsson, R. / Johansson, F. / Homan, E.J. / Loseva, O. / Brautigam, L. / Johansson, L. / Hoglund, A. / Hagenkort, A. / Pham, T. / Altun, M. / Gaugaz, F.Z. / Vikingsson, S. / Evers, B. / Henriksson, M. / Vallin, K.S. / Wallner, O.A. / Hammarstrom, L.G. / Wiita, E. / Almlof, I. / Kalderen, C. / Axelsson, H. / Djureinovic, T. / Puigvert, J.C. / Haggblad, M. / Jeppsson, F. / Martens, U. / Lundin, C. / Lundgren, B. / Granelli, I. / Jensen, A.J. / Artursson, P. / Nilsson, J.A. / Stenmark, P. / Scobie, M. / Berglund, U.W. / Helleday, T.
History
DepositionOct 4, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 16, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 11, 2014Group: Database references
Revision 1.2Aug 5, 2015Group: Structure summary
Revision 1.3Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.4Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,9076
Polymers18,2541
Non-polymers6535
Water2,486138
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)60.378, 66.321, 36.136
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-203-

SO4

21A-372-

HOH

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Components

#1: Protein 7,8-dihydro-8-oxoguanine triphosphatase / 2-hydroxy-dATP diphosphatase / 8-oxo-dGTPase / Nucleoside diphosphate-linked moiety X motif 1 / Nudix motif 1


Mass: 18253.736 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NUDT1, MTH1 / Production host: Escherichia coli (E. coli)
References: UniProt: P36639, 8-oxo-dGTP diphosphatase, 2-hydroxy-dATP diphosphatase
#2: Chemical ChemComp-2GD / 6-(2,3-dichlorophenyl)-N~4~-methylpyrimidine-2,4-diamine


Mass: 269.130 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H10Cl2N4
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 138 / Source method: isolated from a natural source / Formula: H2O

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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: 1.98 Å3/Da / Density % sol: 37.93 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 3.5
Details: 32% PEG 6000, 0.1 M Sodium Acetate pH 3.5, 0.2 M Lithium Sulfate, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jun 27, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.584→44.647 Å / Num. all: 19801 / Num. obs: 19801 / % possible obs: 99.9 % / Redundancy: 4.8 % / Rsym value: 0.059 / Net I/σ(I): 14.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.6-1.694.70.4151.81321027960.41599.4
1.69-1.794.80.2812.61314727130.281100
1.79-1.914.80.1784.11222425240.178100
1.91-2.074.90.1096.61149123650.109100
2.07-2.264.80.0759.11062622020.075100
2.26-2.534.80.06210.6954719830.062100
2.53-2.924.80.04713848717680.047100
2.92-3.584.80.03515.4727115270.035100
3.58-5.064.60.0312.2557312050.03100
5.06-44.6474.20.0291130317180.02999.8

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Processing

Software
NameVersionClassificationNB
SCALA3.3.20data scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3ZR1

3zr1


Resolution: 1.6→44.647 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.948 / WRfactor Rfree: 0.2041 / WRfactor Rwork: 0.1694 / Occupancy max: 1 / Occupancy min: 0.3 / FOM work R set: 0.8754 / SU B: 3.569 / SU ML: 0.063 / SU R Cruickshank DPI: 0.0966 / SU Rfree: 0.0956 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.097 / ESU R Free: 0.096 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2093 986 5 %RANDOM
Rwork0.1751 ---
obs0.1769 19763 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 81.58 Å2 / Biso mean: 17.7065 Å2 / Biso min: 6.99 Å2
Baniso -1Baniso -2Baniso -3
1--1.22 Å20 Å20 Å2
2--0.11 Å2-0 Å2
3---1.11 Å2
Refinement stepCycle: LAST / Resolution: 1.6→44.647 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1254 0 37 138 1429
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0191375
X-RAY DIFFRACTIONr_bond_other_d0.0010.021257
X-RAY DIFFRACTIONr_angle_refined_deg1.531.981870
X-RAY DIFFRACTIONr_angle_other_deg0.73332900
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.285165
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.07524.26568
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.93415233
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.428158
X-RAY DIFFRACTIONr_chiral_restr0.0940.2191
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0211578
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02334
LS refinement shellResolution: 1.6→1.642 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.302 71 -
Rwork0.247 1347 -
all-1418 -
obs--98.61 %
Refinement TLS params.Method: refined / Origin x: 14.3592 Å / Origin y: -13.1638 Å / Origin z: 9.3172 Å
111213212223313233
T0.0794 Å20.0097 Å2-0.0076 Å2-0.0201 Å20.0004 Å2--0.0027 Å2
L1.2779 °20.5004 °2-0.1973 °2-1.2531 °2-0.1731 °2--0.6946 °2
S0.0312 Å °-0.0666 Å °-0.0231 Å °0.0476 Å °-0.0055 Å °0.0112 Å °0.0081 Å °-0.0219 Å °-0.0257 Å °

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