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- PDB-6jvn: Crystal structure of human MTH1 in complex with compound MI1020 -

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Basic information

Entry
Database: PDB / ID: 6jvn
TitleCrystal structure of human MTH1 in complex with compound MI1020
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 / 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 / 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
N4-methyl-6-morpholin-4-yl-pyrimidine-2,4-diamine / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.102 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)36,3614
Polymers35,9432
Non-polymers4182
Water4,432246
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,1812
Polymers17,9711
Non-polymers2091
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)18,1812
Polymers17,9711
Non-polymers2091
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.161, 67.495, 80.053
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
11(chain A and (resid 3 through 13 or resid 18 through 156))
21(chain B and resid 3 through 156)

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ALAALALEULEU(chain A and (resid 3 through 13 or resid 18 through 156))AA3 - 133 - 13
12VALVALVALVAL(chain A and (resid 3 through 13 or resid 18 through 156))AA18 - 15618 - 156
21ALAALAVALVAL(chain B and resid 3 through 156)BB3 - 1563 - 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-CJ0 / N4-methyl-6-morpholin-4-yl-pyrimidine-2,4-diamine


Mass: 209.248 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H15N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 246 / 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: 2.28 Å3/Da / Density % sol: 45.96 % / Mosaicity: 0.609 °
Crystal growTemperature: 298 K / Method: evaporation / pH: 3.75
Details: 30% PEG 6000, 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: BL13C1 / 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: 19185 / % possible obs: 99.5 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.051 / Rpim(I) all: 0.031 / Rrim(I) all: 0.06 / Χ2: 1.062 / Net I/σ(I): 15.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.1-2.183.70.10618800.9870.0640.1241.09599.5
2.18-2.263.60.09418800.990.0570.111.05899.5
2.26-2.373.60.08618960.9920.0520.11.06999.4
2.37-2.493.60.07218850.9940.0430.0841.02799.7
2.49-2.653.60.05918750.9950.0360.071.09799.9
2.65-2.853.60.0519300.9970.030.0581.0799.8
2.85-3.143.60.04319100.9970.0260.051.005100
3.14-3.593.60.04219450.9960.0260.051.08599.8
3.59-4.523.40.04819490.9950.030.0571.00999.2
4.52-303.30.04120350.9960.0260.0481.09998.2

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.102→29.314 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 24.62
RfactorNum. reflection% reflection
Rfree0.2482 1901 10.02 %
Rwork0.1904 --
obs0.1963 18976 98.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 117.5 Å2 / Biso mean: 22.9514 Å2 / Biso min: 2.81 Å2
Refinement stepCycle: final / Resolution: 2.102→29.314 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2476 0 30 246 2752
Biso mean--11.41 28.58 -
Num. residues----305
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A904X-RAY DIFFRACTION1.58TORSIONAL
12B904X-RAY DIFFRACTION1.58TORSIONAL
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 (%)
2.1016-2.15410.26051310.18261169130097
2.1541-2.21230.27151330.1811188132198
2.2123-2.27740.27721340.18871185131998
2.2774-2.35090.30531300.19571192132298
2.3509-2.43490.28981350.2051203133899
2.4349-2.53230.25441330.20191201133499
2.5323-2.64750.25651350.19171206134199
2.6475-2.7870.30781350.2081229136499
2.787-2.96140.28921360.20981222135899
2.9614-3.18980.25021360.20981224136099
3.1898-3.51030.24491390.17771242138199
3.5103-4.01720.23291370.17591241137899
4.0172-5.0570.16441400.15621258139899
5.057-29.31640.26331470.21821315146298
Refinement TLS params.Method: refined / Origin x: 15.8053 Å / Origin y: 0.7219 Å / Origin z: -9.9915 Å
111213212223313233
T0.0156 Å20.0336 Å2-0.0516 Å2-0.0273 Å20.0447 Å2---0.0053 Å2
L0.3864 °2-0.148 °20.114 °2-0.1454 °2-0.0596 °2--0.1829 °2
S0.0158 Å °-0.1634 Å °-0.2828 Å °-0.1101 Å °0.0447 Å °-0.0549 Å °-0.094 Å °0.0529 Å °0.1318 Å °
Refinement TLS groupSelection details: all

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