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- PDB-6jvo: Crystal structure of human MTH1 in complex with compound MI1022 -

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Basic information

Entry
Database: PDB / ID: 6jvo
TitleCrystal structure of human MTH1 in complex with compound MI1022
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 / metal ion binding / nucleus / 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-CJ6 / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.902 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 1.1Nov 18, 2020Group: Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Revision 1.2May 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 1.3Nov 22, 2023Group: 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)36,1774
Polymers35,6812
Non-polymers4972
Water4,432246
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,0892
Polymers17,8401
Non-polymers2481
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)18,0892
Polymers17,8401
Non-polymers2481
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.978, 68.185, 78.901
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 (resseq 3:13 or resseq 18:78 or resseq 80:101 or resseq 103:156))
21(chain B and (resseq 3:13 or resseq 18:78 or resseq 80:101 or resseq 103:156))

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 (resseq 3:13 or resseq 18:78 or resseq 80:101 or resseq 103:156))AA3 - 132 - 12
12VALVALPROPRO(chain A and (resseq 3:13 or resseq 18:78 or resseq 80:101 or resseq 103:156))AA18 - 7817 - 77
13LEULEUMETMET(chain A and (resseq 3:13 or resseq 18:78 or resseq 80:101 or resseq 103:156))AA80 - 10179 - 100
14PROPROVALVAL(chain A and (resseq 3:13 or resseq 18:78 or resseq 80:101 or resseq 103:156))AA103 - 156102 - 155
21ALAALALEULEU(chain B and (resseq 3:13 or resseq 18:78 or resseq 80:101 or resseq 103:156))BB3 - 132 - 12
22VALVALPROPRO(chain B and (resseq 3:13 or resseq 18:78 or resseq 80:101 or resseq 103:156))BB18 - 7817 - 77
23LEULEUMETMET(chain B and (resseq 3:13 or resseq 18:78 or resseq 80:101 or resseq 103:156))BB80 - 10179 - 100
24PROPROVALVAL(chain B and (resseq 3:13 or resseq 18:78 or resseq 80:101 or resseq 103:156))BB103 - 156102 - 155

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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: 17840.266 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 BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): Rosetta
References: UniProt: P36639, 8-oxo-dGTP diphosphatase, 2-hydroxy-dATP diphosphatase
#2: Chemical ChemComp-CJ6 / N4-cyclopropyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine


Mass: 248.327 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H20N6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 246 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 45.55 % / Mosaicity: 0.418 °
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: 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: 1.9→30 Å / Num. obs: 25591 / % possible obs: 99.8 % / Redundancy: 4.4 % / Biso Wilson estimate: 22.15 Å2 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.034 / Rrim(I) all: 0.071 / Χ2: 1.055 / Net I/σ(I): 16.2 / Num. measured all: 112714
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.9-1.974.30.28925230.9450.1550.3291.09599.8
1.97-2.054.40.21125000.9710.1110.2391.023100
2.05-2.144.50.15525050.9860.080.1751.03899.9
2.14-2.254.50.12225530.9920.0640.1381.00599.9
2.25-2.394.50.10925130.9910.0570.1231.04999.7
2.39-2.584.50.08525490.9950.0450.0971.084100
2.58-2.844.50.06725620.9960.0350.0761.043100
2.84-3.254.50.05625650.9970.030.0641.06199.9
3.25-4.094.30.05426000.9960.0290.0611.09899.8
4.09-304.10.03927210.9970.0220.0451.05699.1

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
HKL-2000data scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ZR1

3zr1


Resolution: 1.902→25.795 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 24.44
RfactorNum. reflection% reflection
Rfree0.248 1961 7.84 %
Rwork0.1904 --
obs0.195 25019 97.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 104.16 Å2 / Biso mean: 30.0684 Å2 / Biso min: 9.71 Å2
Refinement stepCycle: final / Resolution: 1.902→25.795 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2476 0 36 246 2758
Biso mean--23.61 38.54 -
Num. residues----305
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072578
X-RAY DIFFRACTIONf_angle_d0.9463484
X-RAY DIFFRACTIONf_chiral_restr0.061360
X-RAY DIFFRACTIONf_plane_restr0.006448
X-RAY DIFFRACTIONf_dihedral_angle_d15.9881504
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1380X-RAY DIFFRACTION8.031TORSIONAL
12B1380X-RAY DIFFRACTION8.031TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.902-1.94950.2811270.2163147390
1.9495-2.00220.2761340.2044160596
2.0022-2.06110.30631360.2036157596
2.0611-2.12760.25831360.1918164197
2.1276-2.20360.25081380.1883161197
2.2036-2.29180.24121390.1917161597
2.2918-2.3960.28421400.1989164698
2.396-2.52220.25081410.1925165399
2.5222-2.68010.27581410.1937167299
2.6801-2.88680.23621400.2011164799
2.8868-3.17680.26721440.20241689100
3.1768-3.63540.23551460.18041708100
3.6354-4.57610.19711450.15721721100
4.5761-25.7950.26251540.2083180299
Refinement TLS params.Method: refined / Origin x: 15.6356 Å / Origin y: 0.2346 Å / Origin z: -10.023 Å
111213212223313233
T0.1483 Å2-0.001 Å20.0043 Å2-0.1543 Å20.0175 Å2--0.0957 Å2
L1.8372 °20.5048 °2-0.0023 °2-0.7637 °2-0.1679 °2--0.1245 °2
S0.0552 Å °-0.2218 Å °-0.1403 Å °0.0006 Å °-0.0312 Å °0.0003 Å °-0.004 Å °-0.0465 Å °-0.0239 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA3 - 156
2X-RAY DIFFRACTION1allB2 - 156
3X-RAY DIFFRACTION1allB200
4X-RAY DIFFRACTION1allA200
5X-RAY DIFFRACTION1allS1 - 246

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