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- PDB-5nhy: BAY-707 in complex with MTH1 -

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Basic information

Entry
Database: PDB / ID: 5nhy
TitleBAY-707 in complex with MTH1
Components7,8-dihydro-8-oxoguanine triphosphatase
KeywordsHYDROLASE / NUDIX / NUCLEOTIDE HYDROLASE / INHIBITOR / ONCOLOGY
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 / hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides / 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity ...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 / hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides / 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity / 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 / cytoplasm / cytosol
Similarity search - Function
Oxidized purine nucleoside triphosphate / NUDIX hydrolase / NUDIX hydrolase, conserved site / Nudix box signature. / Nucleoside Triphosphate Pyrophosphohydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily ...Oxidized purine nucleoside triphosphate / NUDIX hydrolase / NUDIX hydrolase, conserved site / Nudix box signature. / 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
Chem-8XT / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.72 Å
AuthorsEllermann, M. / Eheim, A. / Giese, A. / Bunse, S. / Nowak-Reppel, K. / Neuhaus, R. / Weiske, J. / Quanz, M. / Glasauer, A. / Meyer, H. ...Ellermann, M. / Eheim, A. / Giese, A. / Bunse, S. / Nowak-Reppel, K. / Neuhaus, R. / Weiske, J. / Quanz, M. / Glasauer, A. / Meyer, H. / Queisser, N. / Irlbacher, H. / Bader, B. / Rahm, F. / Viklund, J. / Andersson, M. / Ericsson, U. / Ginman, T. / Forsblom, R. / Lindstrom, J. / Silvander, C. / Tresaugues, L. / Gorjanacz, M.
CitationJournal: ACS Chem. Biol. / Year: 2017
Title: Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target.
Authors: Ellermann, M. / Eheim, A. / Rahm, F. / Viklund, J. / Guenther, J. / Andersson, M. / Ericsson, U. / Forsblom, R. / Ginman, T. / Lindstrom, J. / Silvander, C. / Tresaugues, L. / Giese, A. / ...Authors: Ellermann, M. / Eheim, A. / Rahm, F. / Viklund, J. / Guenther, J. / Andersson, M. / Ericsson, U. / Forsblom, R. / Ginman, T. / Lindstrom, J. / Silvander, C. / Tresaugues, L. / Giese, A. / Bunse, S. / Neuhaus, R. / Weiske, J. / Quanz, M. / Glasauer, A. / Nowak-Reppel, K. / Bader, B. / Irlbacher, H. / Meyer, H. / Queisser, N. / Bauser, M. / Haegebarth, A. / Gorjanacz, M.
History
DepositionMar 22, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 19, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 30, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)38,03314
Polymers36,5072
Non-polymers1,52512
Water2,792155
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,2119
Polymers18,2541
Non-polymers9578
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,8225
Polymers18,2541
Non-polymers5694
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.528, 66.709, 82.075
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 18253.736 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Full length human MTH1 Isoform p18 containing residuals from a thrombin-cleavage site in N-terminus
Source: (gene. exp.) Homo sapiens (human) / Gene: NUDT1, MTH1 / Variant: Isoform p18 / Plasmid: pET-28a / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta phage resistant
References: UniProt: P36639, 8-oxo-dGTP diphosphatase, 2-hydroxy-dATP diphosphatase
#2: Chemical ChemComp-8XT / ~{N}-ethyl-4-[(3~{S})-3-methylmorpholin-4-yl]-1~{H}-pyrrolo[2,3-b]pyridine-2-carboxamide


Mass: 288.345 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H20N4O2
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 155 / 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: 2.24 Å3/Da / Density % sol: 45.12 % / Description: Long and large rods
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 22.7% PEG4000, 0.24 ammonium sulfate, 15% glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.972 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 3, 2017 / Details: mirrors
RadiationMonochromator: Silicon (111) channel-cut / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.972 Å / Relative weight: 1
ReflectionResolution: 1.72→48.19 Å / Num. obs: 35361 / % possible obs: 99.8 % / Redundancy: 5.4 % / Biso Wilson estimate: 30.882 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.032 / Rrim(I) all: 0.074 / Net I/σ(I): 12.4
Reflection shellResolution: 1.72→1.75 Å / Redundancy: 5.6 % / Rmerge(I) obs: 1.298 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1844 / CC1/2: 0.612 / Rpim(I) all: 0.603 / Rrim(I) all: 1.435 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3Q93

3q93


Resolution: 1.72→48.19 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.939 / SU B: 9.498 / SU ML: 0.143 / Cross valid method: THROUGHOUT / ESU R: 0.135 / ESU R Free: 0.132 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26191 1751 5 %RANDOM
Rwork0.22037 ---
obs0.22243 33555 99.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 42.157 Å2
Baniso -1Baniso -2Baniso -3
1--0.15 Å2-0 Å20 Å2
2--0.32 Å2-0 Å2
3----0.16 Å2
Refinement stepCycle: 1 / Resolution: 1.72→48.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2492 0 95 155 2742
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0192669
X-RAY DIFFRACTIONr_bond_other_d0.0030.022423
X-RAY DIFFRACTIONr_angle_refined_deg1.6461.9893613
X-RAY DIFFRACTIONr_angle_other_deg0.92135625
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5035313
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.30924.091132
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.28815451
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.681517
X-RAY DIFFRACTIONr_chiral_restr0.0950.2376
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212930
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02575
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.330.7821231
X-RAY DIFFRACTIONr_mcbond_other0.330.7821230
X-RAY DIFFRACTIONr_mcangle_it0.5381.1711536
X-RAY DIFFRACTIONr_mcangle_other0.5381.1721537
X-RAY DIFFRACTIONr_scbond_it0.9461.091438
X-RAY DIFFRACTIONr_scbond_other0.9441.091438
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.3061.5992073
X-RAY DIFFRACTIONr_long_range_B_refined7.12210.7152879
X-RAY DIFFRACTIONr_long_range_B_other7.12110.742880
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.72→1.765 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.395 112 -
Rwork0.364 2452 -
obs--99.65 %
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)
11.93640.00040.40784.33920.56821.40860.06050.02470.10020.04970.04910.147-0.0085-0.0535-0.10970.02350.0010.02270.0341-0.00810.447-1.515514.427110.1144
27.56933.32932.88246.94433.28751.8570.1384-0.4377-0.01650.2229-0.17270.17330.1139-0.19560.03430.0818-0.02450.07090.11380.03330.4434-8.19110.642712.9195
33.8771-2.12920.8853.5644-1.51842.16050.07250.0669-0.0424-0.1614-0.0910.14710.0357-0.00020.01850.0435-0.0220.0060.0239-0.01570.4949-2.89178.11029.3477
43.4892-0.72553.51877.6569-2.037729.7929-0.0081-0.2101-0.0702-0.21320.09470.5161-0.002-0.6647-0.08660.22930.00840.03590.2255-0.0320.3926-10.063323.467513.0719
52.1733-2.1942-0.23744.7962-0.07362.01-0.01250.07680.27490.0884-0.0412-0.2483-0.13040.14010.05370.0506-0.01860.01090.03510.00520.46687.018217.694311.4534
65.3054-0.59092.81084.0225-1.183410.6703-0.00660.1269-0.2043-0.0765-0.1033-0.04920.08260.02660.10990.00990.00460.03370.0070.00980.43799.1593.11412.0282
714.85740.5454-2.79044.81830.07490.58710.01060.2798-2.70710.4949-0.3049-0.39010.0387-0.00910.29430.10360.0073-0.12580.1074-0.19061.270330.8287-14.85019.4718
89.42762.3695-2.46428.75950.03180.70040.03430.3114-1.033-0.0491-0.274-0.15710.0052-0.08830.23970.34440.0534-0.16950.2979-0.10030.5538.7177-9.90666.5165
99.7868-5.6403-7.860410.07833.65346.71790.68011.0965-0.1441-0.6722-0.6006-0.7424-0.5904-0.5191-0.07950.1872-0.04310.00190.628-0.320.640332.8911-8.53290.6374
1011.1073-2.6764-5.28895.69732.39124.90730.19960.26-1.63090.21710.0124-0.4141-0.05340.0016-0.2120.0265-0.0008-0.11370.0667-0.08590.978932.1096-10.07529.7571
1110.8334.9565-0.02842.89421.78556.3654-0.2370.6471-2.9230.06850.0288-1.04740.4316-0.39450.20820.1336-0.11230.04150.2824-0.45251.703723.7436-20.66196.8223
129.9598-0.38140.06144.2026-2.24355.24460.38410.1511-0.96670.0498-0.18430.0020.1229-0.0796-0.19980.04720.0211-0.06620.0417-0.02570.53920.0777-5.343811.8204
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A3 - 24
2X-RAY DIFFRACTION2A25 - 54
3X-RAY DIFFRACTION3A55 - 92
4X-RAY DIFFRACTION4A93 - 100
5X-RAY DIFFRACTION5A101 - 129
6X-RAY DIFFRACTION6A130 - 156
7X-RAY DIFFRACTION7B3 - 31
8X-RAY DIFFRACTION8B32 - 55
9X-RAY DIFFRACTION9B56 - 70
10X-RAY DIFFRACTION10B71 - 99
11X-RAY DIFFRACTION11B100 - 118
12X-RAY DIFFRACTION12B119 - 156

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