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- PDB-4n1u: Structure of human MTH1 in complex with TH588 -

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Basic information

Entry
Database: PDB / ID: 4n1u
TitleStructure of human MTH1 in complex with TH588
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-2GE / 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)38,05216
Polymers36,3092
Non-polymers1,74314
Water3,927218
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,1229
Polymers18,1551
Non-polymers9688
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,9307
Polymers18,1551
Non-polymers7756
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.658, 66.073, 72.477
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 18154.605 Da / Num. of mol.: 2 / Fragment: UNP residues 42-197
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-2GE / N~4~-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine


Mass: 295.167 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H12Cl2N4
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 218 / 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: 1.9 Å3/Da / Density % sol: 35.3 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 3.5
Details: 22% PEG 6000, 0.1 M Sodium Acetate pH 3.5, 0.2 M Lithium Sulfate, temperature 292K, VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 28, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.595→48.828 Å / Num. all: 37527 / Num. obs: 37527 / % possible obs: 99.8 % / Redundancy: 6.5 % / Rsym value: 0.072 / Net I/σ(I): 17.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.6-1.686.30.6451.23380453390.64598.8
1.68-1.786.50.4641.63334351110.464100
1.78-1.916.70.2952.63234248220.295100
1.91-2.066.40.1764.22876145080.176100
2.06-2.266.80.1146.52812841620.114100
2.26-2.526.70.0888.42539237950.088100
2.52-2.916.50.06311.52179933410.063100
2.91-3.576.70.0417.31911028560.04100
3.57-5.056.40.02525.61443422600.025100
5.05-48.8285.90.02517.7789613330.02599.9

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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→48.828 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.952 / WRfactor Rfree: 0.186 / WRfactor Rwork: 0.165 / Occupancy max: 1 / Occupancy min: 0.25 / FOM work R set: 0.86 / SU B: 4.05 / SU ML: 0.071 / SU R Cruickshank DPI: 0.1016 / SU Rfree: 0.0946 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.102 / ESU R Free: 0.095 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2042 1872 5 %RANDOM
Rwork0.1802 ---
obs0.1814 37468 99.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 75.28 Å2 / Biso mean: 20.4368 Å2 / Biso min: 8.67 Å2
Baniso -1Baniso -2Baniso -3
1--2.27 Å20 Å20 Å2
2--0.03 Å20 Å2
3---2.24 Å2
Refinement stepCycle: LAST / Resolution: 1.6→48.828 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2496 0 98 218 2812
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0192744
X-RAY DIFFRACTIONr_bond_other_d0.0010.022489
X-RAY DIFFRACTIONr_angle_refined_deg1.5781.993733
X-RAY DIFFRACTIONr_angle_other_deg0.72935742
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2425326
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.94124.265136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.78915458
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3181517
X-RAY DIFFRACTIONr_chiral_restr0.0860.2386
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213113
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02656
LS refinement shellResolution: 1.6→1.637 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.272 121 -
Rwork0.271 2528 -
all-2649 -
obs--97.46 %
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)
12.38320.44160.30413.26250.01791.50160.0299-0.0890.28770.10710.08270.199-0.0972-0.1771-0.11260.14450.02040.02640.0584-0.00840.0742-0.79482.10710.276
25.1133.5897-0.73667.16271.53641.8283-0.11750.15350.1441-0.3418-0.04830.6517-0.0583-0.26130.16570.11440.0097-0.03470.04730.00040.1123-10.42973.9335.631
34.353-4.8802-0.17056.5106-0.93473.23670.26430.2891-0.2813-0.4712-0.19680.6931-0.0835-0.0422-0.06750.1738-0.0321-0.10630.06960.03430.2151-5.51979.0881.337
41.3942-0.16620.27423.4906-3.167210.78470.0525-0.0549-0.01410.0298-0.02380.13110.0930.05-0.02870.10760.00650.00960.0697-0.00160.0066-0.28570.83712.454
57.1616-0.212.95314.77981.14452.0195-0.1208-0.21020.6876-0.1827-0.10660.1388-0.1991-0.16250.22740.19640.04290.00420.05220.00160.1382-3.04990.6185.809
63.0585-0.725-1.33633.53480.41362.0985-0.0426-0.06610.4083-0.13730.0367-0.1614-0.07610.04860.00590.1235-0.0143-0.00720.0386-0.01680.081510.27780.8999.841
72.2128-0.4883-2.46421.84110.97829.04080.0048-0.19230.1040.07350.003-0.0472-0.1273-0.0262-0.00770.12380.0182-0.00330.0794-0.00470.00869.21369.64413.121
81.7780.4717-0.53152.6668-0.16051.2633-0.01270.09110.051-0.12810.07130.02720.0845-0.1203-0.05860.164-0.0127-0.01250.06080.00250.028427.04784.46625.729
92.3381-0.0978-0.81632.7378-0.48840.56430.01180.10010.04510.0156-0.00920.22450.0327-0.1627-0.00260.1677-0.0158-0.00670.105-0.02450.073817.42288.3531.17
100.78290.5325-0.95782.4686-2.97526.54190.088-0.01670.13180.1142-0.03890.1286-0.18610.0416-0.04910.1226-0.0097-0.00620.02870.00520.037628.53994.5227.299
112.0283-0.6329-0.64121.8642-0.51031.3542-0.0897-0.0367-0.1632-0.0351-0.01260.02180.2832-0.02870.10230.1607-0.0336-0.00670.0248-0.00470.031625.28875.07129.889
121.86750.30760.76082.25940.8912.4054-0.04390.0135-0.10420.09420.0109-0.07040.16240.00640.0330.151-0.00110.00360.03630.01910.023337.4984.87927.767
131.32770.5429-0.05521.90290.6669.54910.029-0.00040.0593-0.0406-0.01160.01920.06520.0042-0.01740.1278-0.0024-0.01170.05740.01420.023338.27596.00323.91
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A3 - 33
2X-RAY DIFFRACTION2A34 - 51
3X-RAY DIFFRACTION3A52 - 69
4X-RAY DIFFRACTION4A70 - 90
5X-RAY DIFFRACTION5A91 - 107
6X-RAY DIFFRACTION6A108 - 130
7X-RAY DIFFRACTION7A131 - 155
8X-RAY DIFFRACTION8B2 - 34
9X-RAY DIFFRACTION9B35 - 62
10X-RAY DIFFRACTION10B63 - 89
11X-RAY DIFFRACTION11B90 - 109
12X-RAY DIFFRACTION12B110 - 132
13X-RAY DIFFRACTION13B133 - 155

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