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- PDB-5ngr: Crystal structure of human MTH1 in complex with fragment inhibito... -

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Basic information

Entry
Database: PDB / ID: 5ngr
TitleCrystal structure of human MTH1 in complex with fragment inhibitor 8-(methylsulfanyl)-7H-purin-6-amine
Components7,8-dihydro-8-oxoguanine triphosphatase
KeywordsHYDROLASE / Inhibitor / Fragment / Oxidised nucleotides
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 / Phosphate bond hydrolysis by NUDT proteins ...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 / Phosphate bond hydrolysis by NUDT proteins / DNA protection / hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides / purine nucleoside catabolic process / snoRNA binding / Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides / response to oxidative stress / mitochondrial matrix / DNA repair / mitochondrion / metal ion binding / nucleus / cytoplasm / cytosol
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
8-methylsulfanyl-7~{H}-purin-6-amine / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsGustafsson, R. / Rudling, A. / Almlof, I. / Homan, E. / Scobie, M. / Warpman Berglund, U. / Helleday, T. / Carlsson, J. / Stenmark, P.
Funding support Sweden, 13items
OrganizationGrant numberCountry
Swedish e-Science Research Center Sweden
Science for Life Laboratory Sweden
Knut and Alice Wallenberg Foundation Sweden
Wenner-Gren Foundation Sweden
Clas Groschinskys Foundation Sweden
Ake Wiberg Foundation Sweden
Goran Gustafsson Foundation Sweden
Swedish Children's Cancer Foundation Sweden
Swedish Pain Relief Foundation Sweden
Torsten and Ragnar Soderberg Foundation Sweden
Swedish Cancer Society Sweden
Swedish Research Council Sweden
CitationJournal: J. Med. Chem. / Year: 2017
Title: Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space.
Authors: Rudling, A. / Gustafsson, R. / Almlof, I. / Homan, E. / Scobie, M. / Warpman Berglund, U. / Helleday, T. / Stenmark, P. / Carlsson, J.
History
DepositionMar 20, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 4, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 25, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_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)37,44610
Polymers36,5072
Non-polymers9398
Water1,42379
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,8196
Polymers18,2541
Non-polymers5655
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)18,6274
Polymers18,2541
Non-polymers3733
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.902, 67.842, 82.131
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: VAL / End label comp-ID: VAL / Refine code: _ / Auth seq-ID: 3 - 156 / Label seq-ID: 6 - 159

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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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 / 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 BL21(DE3) (bacteria)
References: UniProt: P36639, 8-oxo-dGTP diphosphatase, 2-hydroxy-dATP diphosphatase
#2: Chemical ChemComp-8WT / 8-methylsulfanyl-7~{H}-purin-6-amine


Mass: 181.218 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H7N5S
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.29 Å3/Da / Density % sol: 46.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 5 mmol/L compound and 6 mmol/L MgCl2 were added to MTH1. Sitting drop vapor diffusion experiments at 293K were performed, and MTH1 (9.34 mg/mL) was mixed with reservoir solution (30% (w/v) ...Details: 5 mmol/L compound and 6 mmol/L MgCl2 were added to MTH1. Sitting drop vapor diffusion experiments at 293K were performed, and MTH1 (9.34 mg/mL) was mixed with reservoir solution (30% (w/v) PEG6000, 0.1 mol/L Sodium Acetate pH 3.7 and 0.2 mol/L LiSO4 in a 1:1 ratio.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Dec 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 2.2→48.4 Å / Num. obs: 17597 / % possible obs: 99.9 % / Redundancy: 6.3 % / CC1/2: 0.991 / Rmerge(I) obs: 0.234 / Net I/σ(I): 8.1
Reflection shellResolution: 2.2→2.27 Å / Redundancy: 6.5 % / Rmerge(I) obs: 2.007 / Mean I/σ(I) obs: 2 / Num. unique obs: 1502 / CC1/2: 0.545 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ZR1

3zr1


Resolution: 2.2→48.4 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.919 / SU B: 8.104 / SU ML: 0.196 / Cross valid method: THROUGHOUT / ESU R: 0.311 / ESU R Free: 0.227 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2539 927 5.3 %RANDOM
Rwork0.21036 ---
obs0.21275 16625 99.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 36.83 Å2
Baniso -1Baniso -2Baniso -3
1--1.35 Å20 Å20 Å2
2---1.04 Å20 Å2
3---2.39 Å2
Refinement stepCycle: 1 / Resolution: 2.2→48.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2508 0 54 79 2641
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0192622
X-RAY DIFFRACTIONr_bond_other_d0.0020.022366
X-RAY DIFFRACTIONr_angle_refined_deg1.5411.9563548
X-RAY DIFFRACTIONr_angle_other_deg0.8912.9965486
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0365306
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.76724.242132
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.50715446
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8051516
X-RAY DIFFRACTIONr_chiral_restr0.0880.2368
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212904
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02566
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_it2.8873.4391230
X-RAY DIFFRACTIONr_mcbond_other2.8853.4381229
X-RAY DIFFRACTIONr_mcangle_it4.6955.1481534
X-RAY DIFFRACTIONr_mcangle_other4.6945.1491535
X-RAY DIFFRACTIONr_scbond_it3.8093.9381392
X-RAY DIFFRACTIONr_scbond_other3.683.861369
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.9615.6111979
X-RAY DIFFRACTIONr_long_range_B_refined8.67737.9842712
X-RAY DIFFRACTIONr_long_range_B_other8.67637.9772713
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 9524 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.09 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.293 73 -
Rwork0.3 1212 -
obs--99.84 %

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