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- PDB-6us4: MTH1 in complex with compound 32 -

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Basic information

Entry
Database: PDB / ID: 6us4
TitleMTH1 in complex with compound 32
Components7,8-dihydro-8-oxoguanine triphosphatase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Hydrolase / NUDT1 / Nudix hydrolase / inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
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 / hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides / 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity ...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 / hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides / 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity / 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. / Nucleoside Triphosphate Pyrophosphohydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily ...Oxidized purine nucleoside triphosphate / NUDIX hydrolase / NUDIX hydrolase, conserved site / Nudix box signature. / Nucleoside Triphosphate Pyrophosphohydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-GN6 / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.95032907402 Å
AuthorsNewby, Z.E.R. / Lansdon, E.B.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation.
Authors: Farand, J. / Kropf, J.E. / Blomgren, P. / Xu, J. / Schmitt, A.C. / Newby, Z.E. / Wang, T. / Murakami, E. / Barauskas, O. / Sudhamsu, J. / Feng, J.Y. / Niedziela-Majka, A. / Schultz, B.E. / ...Authors: Farand, J. / Kropf, J.E. / Blomgren, P. / Xu, J. / Schmitt, A.C. / Newby, Z.E. / Wang, T. / Murakami, E. / Barauskas, O. / Sudhamsu, J. / Feng, J.Y. / Niedziela-Majka, A. / Schultz, B.E. / Schwartz, K. / Viatchenko-Karpinski, S. / Kornyeyev, D. / Kashishian, A. / Fan, P. / Chen, X. / Lansdon, E.B. / Ports, M.O. / Currie, K.S. / Watkins, W.J. / Notte, G.T.
History
DepositionOct 24, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 1, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5332
Polymers18,2541
Non-polymers2791
Water1,36976
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area8080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)36.235, 60.365, 66.286
Angle α, β, γ (deg.)90.0, 90.0, 90.0
Int Tables number18
Space group name H-MP22121
Space group name HallP22ab(z,x,y)
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y+1/2,-z+1/2
#4: -x,-y+1/2,z+1/2

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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: 18253.736 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NUDT1, MTH1 / Production host: Escherichia coli (E. coli)
References: UniProt: P36639, 8-oxo-dGTP diphosphatase, 2-hydroxy-dATP diphosphatase
#2: Chemical ChemComp-GN6 / 5-(2,3-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine


Mass: 279.125 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H8Cl2N4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 76 / 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: 1.99 Å3/Da / Density % sol: 38.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 30% PEG 6000, 0.1M sodium acetate pH 4.0, 0.2M lithium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Aug 25, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 11103 / % possible obs: 99.7 % / Redundancy: 3.3 % / Biso Wilson estimate: 18.8172733101 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 13
Reflection shellResolution: 1.95→1.98 Å / Rmerge(I) obs: 0.526 / Num. unique obs: 531

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ZR0

3zr0


Resolution: 1.95032907402→31.7946031486 Å / SU ML: 0.218717161044 / Cross valid method: THROUGHOUT / σ(F): 0.177178828439 / Phase error: 21.2264873085
RfactorNum. reflection% reflection
Rfree0.244401912066 1049 10.00381461 %
Rwork0.175057190813 --
obs0.1819376565 10486 94.4174320187 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 21.2333500652 Å2
Refinement stepCycle: LAST / Resolution: 1.95032907402→31.7946031486 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1254 0 18 76 1348
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00703831947961336
X-RAY DIFFRACTIONf_angle_d1.082110157471815
X-RAY DIFFRACTIONf_chiral_restr0.0474962078264187
X-RAY DIFFRACTIONf_plane_restr0.00628636616768235
X-RAY DIFFRACTIONf_dihedral_angle_d13.8919834603496
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95032907402-2.05310.2637632147321340.1817331618971204X-RAY DIFFRACTION86.3225806452
2.0531-2.18170.2943302421941450.1791741649311302X-RAY DIFFRACTION93.8391699092
2.1817-2.35010.2578513023741480.1757422087541329X-RAY DIFFRACTION93.8970120788
2.3501-2.58660.2719753797361500.1870757252551350X-RAY DIFFRACTION95.6022944551
2.5866-2.96060.2594437805511500.1953928042731356X-RAY DIFFRACTION96.2915601023
2.9606-3.72910.2265745185051570.1652427248861421X-RAY DIFFRACTION97.7695167286
3.7291-31.79460314860.2172154910891650.1656210773121475X-RAY DIFFRACTION96.8122786305

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