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- PDB-6jvq: Crystal structure of human MTH1 in complex with compound MI1025 -

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Basic information

Entry
Database: PDB / ID: 6jvq
TitleCrystal structure of human MTH1 in complex with compound MI1025
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-CJF / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.197 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)36,4134
Polymers35,9432
Non-polymers4712
Water2,648147
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2072
Polymers17,9711
Non-polymers2351
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)18,2072
Polymers17,9711
Non-polymers2351
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.122, 68.780, 78.874
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 18:24 or resseq...
21(chain B and (resseq 3:13 or resseq 18:24 or resseq...

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 18:24 or resseq...AA3 - 133 - 13
12VALVALLYSLYS(chain A and (resseq 3:13 or resseq 18:24 or resseq...AA18 - 2418 - 24
13GLYGLYPROPRO(chain A and (resseq 3:13 or resseq 18:24 or resseq...AA26 - 7826 - 78
14ARGARGARGARG(chain A and (resseq 3:13 or resseq 18:24 or resseq...AA151151
15ALAALAVALVAL(chain A and (resseq 3:13 or resseq 18:24 or resseq...AA3 - 1563 - 156
16VALVALVALVAL(chain A and (resseq 3:13 or resseq 18:24 or resseq...AA153 - 156153 - 156
21ALAALALEULEU(chain B and (resseq 3:13 or resseq 18:24 or resseq...BB3 - 133 - 13
22VALVALLYSLYS(chain B and (resseq 3:13 or resseq 18:24 or resseq...BB18 - 2418 - 24
23GLYGLYPROPRO(chain B and (resseq 3:13 or resseq 18:24 or resseq...BB26 - 7826 - 78
24LEULEUPHEPHE(chain B and (resseq 3:13 or resseq 18:24 or resseq...BB80 - 11380 - 113
25ASPASPARGARG(chain B and (resseq 3:13 or resseq 18:24 or resseq...BB115 - 151115 - 151
26VALVALVALVAL(chain B and (resseq 3:13 or resseq 18:24 or resseq...BB153 - 156153 - 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-CJF / N4-cyclopropyl-6-morpholin-4-yl-pyrimidine-2,4-diamine


Mass: 235.286 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H17N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 147 / 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: 46.14 % / Mosaicity: 2.283 °
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
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: 2.197→30 Å / Num. obs: 16523 / % possible obs: 97.3 % / Redundancy: 3.3 % / Biso Wilson estimate: 31.53 Å2 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.063 / Rrim(I) all: 0.115 / Χ2: 1.075 / Net I/σ(I): 9.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.2-2.283.10.33116450.8880.2210.4011.09699.4
2.28-2.373.20.31716480.90.210.3831.06599.2
2.37-2.483.30.2816600.9270.1830.3361.09999.4
2.48-2.613.30.22316660.9510.1450.2671.08599.3
2.61-2.773.30.18516370.9540.1220.2241.09698.4
2.77-2.993.30.14916730.9530.0990.181.09298.5
2.99-3.293.30.11916300.9710.080.1441.07696.6
3.29-3.763.30.09116320.9840.0610.111.03495.6
3.76-4.733.30.06916240.9860.0470.0841.02694.5
4.73-303.30.0617080.9910.040.0721.08493

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.197→27.817 Å / SU ML: 0.29 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 29.27 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2663 1605 9.98 %
Rwork0.1956 14485 -
obs0.2027 16090 94.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 108.56 Å2 / Biso mean: 39.1969 Å2 / Biso min: 15 Å2
Refinement stepCycle: final / Resolution: 2.197→27.817 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2476 0 34 147 2657
Biso mean--30.62 43.58 -
Num. residues----305
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072576
X-RAY DIFFRACTIONf_angle_d0.973480
X-RAY DIFFRACTIONf_chiral_restr0.06360
X-RAY DIFFRACTIONf_plane_restr0.007448
X-RAY DIFFRACTIONf_dihedral_angle_d17.5811502
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1324X-RAY DIFFRACTION9.585TORSIONAL
12B1324X-RAY DIFFRACTION9.585TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1971-2.2680.29781400.20991255139592
2.268-2.3490.30951410.21541261140294
2.349-2.4430.32061420.20781295143795
2.443-2.55410.34081440.20911318146296
2.5541-2.68860.33331470.21361335148297
2.6886-2.85690.29081470.21021308145596
2.8569-3.07730.30151460.22071345149197
3.0773-3.38640.28971470.20341315146296
3.3864-3.87530.22771480.18091327147595
3.8753-4.87820.20411480.15821331147994
4.8782-27.81890.25541550.20561395155093
Refinement TLS params.Method: refined / Origin x: 15.728 Å / Origin y: 0.197 Å / Origin z: -9.9708 Å
111213212223313233
T0.2088 Å2-0.0128 Å20.0056 Å2-0.2274 Å20.0326 Å2--0.1657 Å2
L1.3009 °2-0.0039 °20.2737 °2-0.2888 °2-0.0986 °2---0.1217 °2
S0.0439 Å °-0.2458 Å °-0.2123 Å °-0.0547 Å °-0.0148 Å °-0.0039 Å °-0.0257 Å °-0.0311 Å °0.01 Å °
Refinement TLS groupSelection details: all

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