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- PDB-6jvk: Crystal structure of human MTH1 in complex with compound MI1012 -

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Basic information

Entry
Database: PDB / ID: 6jvk
TitleCrystal structure of human MTH1 in complex with compound MI1012
Components7,8-dihydro-8-oxoguanine triphosphatase
KeywordsHYDROLASE / MTH1 / Oxidative DNA damage / 8-oxo-dGTP / Inhibitor development
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 / DNA protection ...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 / DNA protection / hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides / 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 / NUDIX hydrolase, conserved site / Nudix box signature. / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily
Similarity search - Domain/homology
Chem-CEU / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsPeng, C. / Li, Y.H. / Cheng, Y.S.
CitationJournal: Bioorg.Chem. / Year: 2021
Title: Inhibitor development of MTH1 via high-throughput screening with fragment based library and MTH1 substrate binding cavity.
Authors: Peng, C. / Li, Y.H. / Yu, C.W. / Cheng, Z.H. / Liu, J.R. / Hsu, J.L. / Hsin, L.W. / Huang, C.T. / Juan, H.F. / Chern, J.W. / Cheng, Y.S.
History
DepositionApr 17, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 28, 2020Provider: repository / Type: Initial release
Revision 1.1May 12, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 27, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)36,1653
Polymers35,9432
Non-polymers2221
Water4,684260
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,1942
Polymers17,9711
Non-polymers2221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: 7,8-dihydro-8-oxoguanine triphosphatase


Theoretical massNumber of molelcules
Total (without water)17,9711
Polymers17,9711
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.028, 67.780, 79.592
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / End auth comp-ID: VAL / End label comp-ID: VAL

Dom-IDBeg auth comp-IDBeg label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1ALAALAchain AAA3 - 1563 - 156
2GLYGLYchain BBB2 - 1562 - 156

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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: 17971.461 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NUDT1, MTH1 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta(DE3)
References: UniProt: P36639, 8-oxo-dGTP diphosphatase, 2-hydroxy-dATP diphosphatase
#2: Chemical ChemComp-CEU / N4-methyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine


Mass: 222.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H18N6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 260 / 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: 2.26 Å3/Da / Density % sol: 45.5 % / Mosaicity: 0.376 °
Crystal growTemperature: 298 K / Method: evaporation / pH: 3.75
Details: 30% PEG6000, 200 mM Lithium sulphate, 100 mM Sodium acetate pH 3.75

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL13B1 / Wavelength: 1 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Oct 2, 2018 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→30 Å / Num. obs: 19183 / % possible obs: 99.7 % / Redundancy: 4.6 % / Biso Wilson estimate: 22.83 Å2 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.035 / Rrim(I) all: 0.075 / Χ2: 1.054 / Net I/σ(I): 11.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.1-2.184.40.26218490.9390.1380.2971.08898.9
2.18-2.264.60.21318990.9650.110.241.06299.8
2.26-2.374.70.218890.9680.1030.2261.07100
2.37-2.494.70.1618910.9810.0830.1811.08599.9
2.49-2.654.70.12318860.9870.0630.1391.031100
2.65-2.854.70.09719100.9920.050.1091.0199.5
2.85-3.144.60.07319020.9960.0380.0821.09599.9
3.14-3.594.50.05619470.9960.0290.0631.027100
3.59-4.524.40.03819580.9980.020.0441.06799.7
4.52-304.30.03120520.9990.0170.0361.00499.2

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→23.706 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.14
RfactorNum. reflection% reflection
Rfree0.2499 1914 10 %
Rwork0.1825 --
obs0.1893 19133 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 87.34 Å2 / Biso mean: 27.003 Å2 / Biso min: 11.68 Å2
Refinement stepCycle: final / Resolution: 2.1→23.706 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2476 0 16 260 2752
Biso mean--29.83 32.98 -
Num. residues----305
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082555
X-RAY DIFFRACTIONf_angle_d1.1453451
X-RAY DIFFRACTIONf_chiral_restr0.048358
X-RAY DIFFRACTIONf_plane_restr0.006447
X-RAY DIFFRACTIONf_dihedral_angle_d13.829942
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1366X-RAY DIFFRACTION5.498TORSIONAL
12B1366X-RAY DIFFRACTION5.498TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1005-2.1530.31451310.20961182131398
2.153-2.21110.27741330.197611981331100
2.2111-2.27620.27311370.195212211358100
2.2762-2.34960.29581340.187912121346100
2.3496-2.43350.31931360.203112221358100
2.4335-2.53080.26151330.194312011334100
2.5308-2.64580.29161360.195312171353100
2.6458-2.78510.28731360.203612251361100
2.7851-2.95930.28561360.198412301366100
2.9593-3.18730.26431370.19212321369100
3.1873-3.50710.26011380.164112381376100
3.5071-4.01250.19331380.154812511389100
4.0125-5.04730.18481410.143312541395100
5.0473-23.70760.24341480.212913361484100
Refinement TLS params.Method: refined / Origin x: -13.5207 Å / Origin y: -0.5829 Å / Origin z: 10.1464 Å
111213212223313233
T0.1753 Å2-0.0135 Å2-0.0053 Å2-0.1642 Å20.0044 Å2--0.1359 Å2
L1.775 °2-0.6809 °20.0128 °2-0.7283 °2-0.1062 °2--0.1629 °2
S0.0167 Å °0.1201 Å °0.1679 Å °0.0196 Å °-0.0182 Å °-0.0049 Å °-0.0074 Å °-0.0268 Å °0.006 Å °
Refinement TLS groupSelection details: all

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