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- PDB-6jvm: Crystal structure of human MTH1 in complex with compound MI1016 -

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Basic information

Entry
Database: PDB / ID: 6jvm
TitleCrystal structure of human MTH1 in complex with compound MI1016
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 / 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 / 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-CGX / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.098 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)36,2043
Polymers35,9432
Non-polymers2611
Water3,873215
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2332
Polymers17,9711
Non-polymers2611
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)59.097, 67.702, 79.872
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-CGX / N4-cyclopropyl-5-ethyl-6-piperidin-1-yl-pyrimidine-2,4-diamine


Mass: 261.366 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H23N5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 215 / 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: 45.94 % / Mosaicity: 0.554 °
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: 2.098→30 Å / Num. obs: 19277 / % possible obs: 99.6 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.113 / Rpim(I) all: 0.069 / Rrim(I) all: 0.133 / Χ2: 1.077 / Net I/σ(I): 7.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.1-2.183.70.38418660.8570.230.4491.06699.8
2.18-2.263.80.32619110.8810.1950.3811.09299.8
2.26-2.373.80.30419160.8890.1810.3561.08799.8
2.37-2.493.80.26118850.9250.1560.3051.08499.8
2.49-2.653.80.20618920.9450.1230.2411.09799.9
2.65-2.853.80.17619330.9590.1050.2051.0999.6
2.85-3.143.70.13619050.9740.0810.1591.09199.7
3.14-3.593.60.09819560.9830.0610.1161.07899.6
3.59-4.523.50.06719600.9920.0420.0791.01699.1
4.52-303.40.06720530.9920.0430.081.05898.8

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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: 2.098→27.713 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 26.26
RfactorNum. reflection% reflection
Rfree0.2569 1862 10.05 %
Rwork0.1963 --
obs0.2025 18527 95.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 103.13 Å2 / Biso mean: 30.4818 Å2 / Biso min: 11.78 Å2
Refinement stepCycle: final / Resolution: 2.098→27.713 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2476 0 19 215 2710
Biso mean--29.47 35.07 -
Num. residues----305
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A904X-RAY DIFFRACTION1.619TORSIONAL
12B904X-RAY DIFFRACTION1.619TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0978-2.15450.33421320.24511186131891
2.1545-2.21790.27671360.22061236137295
2.2179-2.28950.32141440.21581232137694
2.2895-2.37120.29131410.21881240138194
2.3712-2.46610.31181360.21731241137794
2.4661-2.57830.2921420.21491268141096
2.5783-2.71410.27891390.21111262140195
2.7141-2.8840.29961410.2071250139195
2.884-3.10640.28821470.21111320146797
3.1064-3.41850.25081470.17461317146499
3.4185-3.9120.19061470.16771340148799
3.912-4.92420.17751510.14931350150198
4.9242-27.71530.28421590.22851423158299
Refinement TLS params.Method: refined / Origin x: 15.6663 Å / Origin y: 0.56 Å / Origin z: -9.9015 Å
111213212223313233
T0.1892 Å20.002 Å2-0.0069 Å2-0.1813 Å20.0226 Å2--0.1563 Å2
L2.1395 °20.2246 °20.0994 °2-0.5511 °2-0.1201 °2--0.2116 °2
S0.0648 Å °-0.1554 Å °-0.3317 Å °0.0007 Å °-0.0221 Å °0.0457 Å °-0.0033 Å °-0.0692 Å °-0.0377 Å °
Refinement TLS groupSelection details: all

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