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- PDB-6f22: Complex between MTH1 and compound 29 (a 4-amino-2,7-diazaindole d... -

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Basic information

Entry
Database: PDB / ID: 6f22
TitleComplex between MTH1 and compound 29 (a 4-amino-2,7-diazaindole 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 / DNA protection ...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 / DNA protection / hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides / 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 / nucleus / metal ion binding / cytosol / cytoplasm
Similarity search - Function
Oxidized purine nucleoside triphosphate / NUDIX hydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / NUDIX hydrolase, conserved site / Nudix box signature. / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily ...Oxidized purine nucleoside triphosphate / NUDIX hydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / Nucleoside Triphosphate Pyrophosphohydrolase / NUDIX hydrolase, conserved site / Nudix box signature. / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-C9B / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 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)38,02914
Polymers36,5072
Non-polymers1,52112
Water3,171176
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0147
Polymers18,2541
Non-polymers7616
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)19,0147
Polymers18,2541
Non-polymers7616
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.466, 66.626, 83.076
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NUDT1, MTH1 / Variant: ISOFORM P18 / Plasmid: Plasmid / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta phage resistant
References: UniProt: P36639, 8-oxo-dGTP diphosphatase, 2-hydroxy-dATP diphosphatase
#2: Chemical ChemComp-C9B / (3~{S})-3-phenyl-4-(2~{H}-pyrazolo[3,4-b]pyridin-4-yl)morpholine


Mass: 280.324 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H16N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 176 / 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: 2.25 Å3/Da / Density % sol: 45.43 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 22% PEG4K, 0.24M AmSO4, 12.5% glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.97295 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 25, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97295 Å / Relative weight: 1
ReflectionResolution: 1.55→51.98 Å / Num. obs: 48090 / % possible obs: 99.1 % / Redundancy: 4.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.037 / Rrim(I) all: 0.079 / Net I/σ(I): 12.8
Reflection shellResolution: 1.55→1.58 Å / Rmerge(I) obs: 0.904 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 2321 / CC1/2: 0.555 / Rpim(I) all: 0.481 / Rrim(I) all: 1.028 / % possible all: 98.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5nhy

5nhy


Resolution: 1.55→51.98 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.955 / Cross valid method: THROUGHOUT / ESU R: 0.101 / ESU R Free: 0.081 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20546 2326 4.8 %RANDOM
Rwork0.16941 ---
obs0.17118 45708 98.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 18.783 Å2
Baniso -1Baniso -2Baniso -3
1--0.95 Å2-0 Å2-0 Å2
2---0.24 Å20 Å2
3---1.18 Å2
Refinement stepCycle: 1 / Resolution: 1.55→51.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2530 0 92 176 2798
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192733
X-RAY DIFFRACTIONr_bond_other_d0.0020.022437
X-RAY DIFFRACTIONr_angle_refined_deg1.3591.9893711
X-RAY DIFFRACTIONr_angle_other_deg3.61735664
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4375323
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.89524.148135
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.31615459
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.8211517
X-RAY DIFFRACTIONr_chiral_restr0.0780.2381
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213029
X-RAY DIFFRACTIONr_gen_planes_other0.0060.02578
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_it1.6331.641271
X-RAY DIFFRACTIONr_mcbond_other1.6311.6391270
X-RAY DIFFRACTIONr_mcangle_it2.2062.4661595
X-RAY DIFFRACTIONr_mcangle_other2.2072.4661596
X-RAY DIFFRACTIONr_scbond_it1.9132.0011462
X-RAY DIFFRACTIONr_scbond_other1.8831.9731443
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.3892.8542085
X-RAY DIFFRACTIONr_long_range_B_refined3.21419.5112905
X-RAY DIFFRACTIONr_long_range_B_other3.17119.4052896
X-RAY DIFFRACTIONr_rigid_bond_restr13.0335170
X-RAY DIFFRACTIONr_sphericity_free24.2635113
X-RAY DIFFRACTIONr_sphericity_bonded8.21555165
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 170 -
Rwork0.271 3320 -
obs--98.95 %

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