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- PDB-6jvl: Crystal structure of human MTH1 in complex with compound MI1014 -

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Basic information

Entry
Database: PDB / ID: 6jvl
TitleCrystal structure of human MTH1 in complex with compound MI1014
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-CG0 / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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)36,2193
Polymers35,9432
Non-polymers2761
Water4,684260
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2482
Polymers17,9711
Non-polymers2761
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)59.244, 67.227, 79.583
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-CG0 / N4-cyclopropyl-5-ethyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine


Mass: 276.381 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H24N6
#3: Water ChemComp-HOH / water / 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% 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: 25739 / % possible obs: 99.6 % / Redundancy: 4 % / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.033 / Rrim(I) all: 0.066 / Χ2: 1.069 / Net I/σ(I): 14.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.9-1.973.90.31725280.9060.1830.3681.09999.5
1.97-2.053.90.22125500.9470.1260.2551.09499.6
2.05-2.1440.16525160.9760.0920.1891.09999.8
2.14-2.2540.12925400.9840.0730.1491.089100
2.25-2.3940.11725530.9880.0660.1351.0799.8
2.39-2.5840.0925680.9930.0510.1031.07899.9
2.58-2.8440.06625770.9960.0370.0761.03100
2.84-3.2540.04825750.9980.0270.0551.06699.8
3.25-4.093.90.04126250.9960.0240.0481.00599.8
4.09-303.70.02927070.9980.0170.0341.06897.8

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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: 1.9→27.761 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 22.89
RfactorNum. reflection% reflection
Rfree0.2473 1951 7.77 %
Rwork0.1933 --
obs0.1975 25107 97.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 91.8 Å2 / Biso mean: 28.278 Å2 / Biso min: 9.64 Å2
Refinement stepCycle: final / Resolution: 1.9→27.761 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2476 0 20 260 2756
Biso mean--48.48 36.43 -
Num. residues----305
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A904X-RAY DIFFRACTION2.469TORSIONAL
12B904X-RAY DIFFRACTION2.469TORSIONAL
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 (%)
1.8967-1.94420.2631250.22441501162689
1.9442-1.99670.27461370.20441576171395
1.9967-2.05540.26551340.19471593172796
2.0554-2.12180.23431340.18541639177397
2.1218-2.19760.22081390.17751646178598
2.1976-2.28550.21941370.1791622175997
2.2855-2.38950.2611390.19051668180798
2.3895-2.51540.25261390.20391642178198
2.5154-2.67290.25881410.20051671181298
2.6729-2.8790.26661400.21571662180298
2.879-3.16840.29281440.21231699184399
3.1684-3.6260.26781440.181717161860100
3.626-4.56510.20891470.16051729187699
4.5651-27.76420.23441510.2141792194398
Refinement TLS params.Method: refined / Origin x: 16.0722 Å / Origin y: 0.7518 Å / Origin z: -9.9328 Å
111213212223313233
T0.1438 Å20.0078 Å20.0004 Å2-0.1354 Å20.012 Å2--0.1032 Å2
L1.9351 °20.4478 °20.0602 °2-0.6125 °2-0.0585 °2--0.1395 °2
S0.0125 Å °-0.1291 Å °-0.2421 Å °-0.0409 Å °0.0017 Å °-0.0085 Å °-0.0119 Å °-0.0453 Å °-0.0189 Å °
Refinement TLS groupSelection details: all

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