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- PDB-6f20: Complex between MTH1 and compound 1 (a 7-azaindole-4-ester derivative) -

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Basic information

Entry
Database: PDB / ID: 6f20
TitleComplex between MTH1 and compound 1 (a 7-azaindole-4-ester derivative)
Components7,8-dihydro-8-oxoguanine triphosphatase
KeywordsHYDROLASE / NUDIX / NUCLEOTIDE HYDROLASE / INHIBITOR / ONCOLOGY
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. / 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
ACETATE ION / Ethyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsViklund, J. / Talagas, A. / Tresaugues, L. / Andersson, M. / Ericsson, U. / Forsblom, R. / Ginman, T. / Hallberg, K. / Lindstrom, J. / Persson, L. ...Viklund, J. / Talagas, A. / Tresaugues, L. / Andersson, M. / Ericsson, U. / Forsblom, R. / Ginman, T. / Hallberg, K. / Lindstrom, J. / Persson, L. / Silvander, C. / Rahm, F.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.
Authors: Rahm, F. / Viklund, J. / Tresaugues, L. / Ellermann, M. / Giese, A. / Ericsson, U. / Forsblom, R. / Ginman, T. / Gunther, J. / Hallberg, K. / Lindstrom, J. / Persson, L.B. / Silvander, C. / ...Authors: Rahm, F. / Viklund, J. / Tresaugues, L. / Ellermann, M. / Giese, A. / Ericsson, U. / Forsblom, R. / Ginman, T. / Gunther, J. / Hallberg, K. / Lindstrom, J. / Persson, L.B. / Silvander, C. / Talagas, A. / Diaz-Saez, L. / Fedorov, O. / Huber, K.V.M. / Panagakou, I. / Siejka, P. / Gorjanacz, M. / Bauser, M. / Andersson, M.
History
DepositionNov 23, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 7, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 4, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 17, 2024Group: 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
B: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,73314
Polymers36,5072
Non-polymers1,22612
Water1,78399
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0429
Polymers18,2541
Non-polymers7898
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)18,6915
Polymers18,2541
Non-polymers4374
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)60.150, 68.220, 82.620
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NUDT1, MTH1 / Variant: ISOFORM P18 / Plasmid: PET-28A / Production host: Escherichia coli (E. coli) / Strain (production host): ROSETTA PHAGE RESISTANT
References: UniProt: P36639, 8-oxo-dGTP diphosphatase, 2-hydroxy-dATP diphosphatase

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Non-polymers , 5 types, 111 molecules

#2: Chemical ChemComp-C9E / Ethyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate


Mass: 190.199 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H10N2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 99 / 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: 2.32 Å3/Da / Density % sol: 47.02 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 3.6
Details: 27% PEG6000, 0.3M Lithium sulfate, 0.1M sodium acetate pH=3.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.972 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 3, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.972 Å / Relative weight: 1
ReflectionResolution: 2→48.63 Å / Num. obs: 23476 / % possible obs: 98.9 % / Redundancy: 4.97 % / CC1/2: 0.999 / Rmerge(I) obs: 0.041 / Rrim(I) all: 0.046 / Net I/σ(I): 24.08
Reflection shellResolution: 2→2.11 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.213 / Mean I/σ(I) obs: 8.14 / Num. unique obs: 3641 / CC1/2: 0.975 / Rrim(I) all: 0.24 / % possible all: 96.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XDSdata scaling
PHASER2.7.17phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5NHY

5nhy


Resolution: 2→48.63 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.939 / SU B: 4.762 / SU ML: 0.128 / Cross valid method: THROUGHOUT / ESU R: 0.194 / ESU R Free: 0.167 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23518 1174 5 %RANDOM
Rwork0.19727 ---
obs0.19921 22301 98.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 30.722 Å2
Baniso -1Baniso -2Baniso -3
1--2.53 Å2-0 Å2-0 Å2
2---1.58 Å20 Å2
3---4.12 Å2
Refinement stepCycle: 1 / Resolution: 2→48.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2515 0 76 99 2690
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0192651
X-RAY DIFFRACTIONr_bond_other_d0.0020.022397
X-RAY DIFFRACTIONr_angle_refined_deg1.6251.9813581
X-RAY DIFFRACTIONr_angle_other_deg0.88635560
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5435309
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.42324.242132
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.64115450
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.0381516
X-RAY DIFFRACTIONr_chiral_restr0.0970.2370
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212912
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02570
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.2922.8311239
X-RAY DIFFRACTIONr_mcbond_other2.2922.8291237
X-RAY DIFFRACTIONr_mcangle_it3.3454.2241542
X-RAY DIFFRACTIONr_mcangle_other3.3444.2251543
X-RAY DIFFRACTIONr_scbond_it3.0143.2921412
X-RAY DIFFRACTIONr_scbond_other3.0133.2931413
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.6824.7922039
X-RAY DIFFRACTIONr_long_range_B_refined6.04131.0252612
X-RAY DIFFRACTIONr_long_range_B_other6.04630.9622605
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.997→2.048 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.35 80 -
Rwork0.289 1528 -
obs--93.82 %

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