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- PDB-6f23: Complex between MTH1 and compound 16 (a 4-amino-7-azaindole deriv... -

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Basic information

Entry
Database: PDB / ID: 6f23
TitleComplex between MTH1 and compound 16 (a 4-amino-7-azaindole 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 / 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 / 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-C8Z / Oxidized purine nucleoside triphosphate hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.84 Å
AuthorsViklund, J. / Tresaugues, L. / Talagas, A. / Andersson, M. / Ericsson, U. / Forsblom, R. / Ginman, T. / Hallberg, K. / Lindstrom, J. / Persson, L. ...Viklund, J. / Tresaugues, L. / Talagas, A. / 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)38,27517
Polymers36,5072
Non-polymers1,76815
Water3,585199
1
A: 7,8-dihydro-8-oxoguanine triphosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,1829
Polymers18,2541
Non-polymers9288
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)19,0938
Polymers18,2541
Non-polymers8407
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.420, 67.080, 83.410
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: pET-28a / Production host: Escherichia coli (E. coli)
References: UniProt: P36639, 8-oxo-dGTP diphosphatase, 2-hydroxy-dATP diphosphatase
#2: Chemical ChemComp-C8Z / 4-[(2~{R})-2-phenylpyrrolidin-1-yl]-1~{H}-pyrrolo[2,3-b]pyridine


Mass: 263.337 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H17N3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 199 / 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: 46.2 % / Description: Flat rod
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 3.6
Details: 23% PEG 6000, 0.28M 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: 0.972957 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Nov 14, 2014 / Details: Toroidal mirror
RadiationMonochromator: Silicon (111) crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.972957 Å / Relative weight: 1
ReflectionResolution: 1.84→48.4 Å / Num. obs: 29541 / % possible obs: 99.7 % / Redundancy: 6.5 % / CC1/2: 0.996 / Rmerge(I) obs: 0.148 / Rpim(I) all: 0.063 / Net I/av σ(I): 7.9 / Net I/σ(I): 3.9
Reflection shellResolution: 1.84→1.9 Å / Redundancy: 6 % / Rmerge(I) obs: 1.877 / Mean I/σ(I) obs: 0.5 / Num. unique obs: 2846 / CC1/2: 0.518 / Rpim(I) all: 0.832 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3Q93

3q93


Resolution: 1.84→48.4 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.929 / SU B: 9.801 / SU ML: 0.143 / Cross valid method: THROUGHOUT / ESU R: 0.173 / ESU R Free: 0.155 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25872 1443 4.9 %RANDOM
Rwork0.22114 ---
obs0.22305 28037 99.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 30.885 Å2
Baniso -1Baniso -2Baniso -3
1-0.32 Å20 Å20 Å2
2--0.31 Å2-0 Å2
3----0.63 Å2
Refinement stepCycle: 1 / Resolution: 1.84→48.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2540 0 107 199 2846
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0192742
X-RAY DIFFRACTIONr_bond_other_d0.0020.022456
X-RAY DIFFRACTIONr_angle_refined_deg1.5591.9933718
X-RAY DIFFRACTIONr_angle_other_deg0.88935711
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6355323
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.69624.254134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.48415461
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5711516
X-RAY DIFFRACTIONr_chiral_restr0.0870.2385
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213015
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02593
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_it0.2530.8331268
X-RAY DIFFRACTIONr_mcbond_other0.2530.8331267
X-RAY DIFFRACTIONr_mcangle_it0.4321.2491587
X-RAY DIFFRACTIONr_mcangle_other0.4321.2491588
X-RAY DIFFRACTIONr_scbond_it0.6941.061474
X-RAY DIFFRACTIONr_scbond_other0.6941.061474
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.9481.5682128
X-RAY DIFFRACTIONr_long_range_B_refined5.83910.7922921
X-RAY DIFFRACTIONr_long_range_B_other5.83910.7872921
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.84→1.888 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.501 92 -
Rwork0.53 2025 -
obs--98.74 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.2062-1.0728-0.49693.16680.53611.75130.06610.11170.0711-0.2644-0.03820.1061-0.07360.0064-0.02790.0244-0.0024-0.02610.06180.0020.2625-3.1673-10.5942-13.0406
22.29970.7268-0.49612.605-0.31110.64590.0353-0.0789-0.03110.0169-0.01570.07660.05760.0203-0.01960.010.005-0.01720.0576-00.2681.7-10.5714-10.8203
39.5791-1.44541.31644.23410.5710.33360.1313-0.30451.5827-0.3568-0.2959-0.3184-0.0487-0.08830.16460.03320.02070.06240.1299-0.1030.626134.210412.7296-7.5286
46.2911.06671.27472.65280.50840.41850.0988-0.2251.1027-0.04-0.0823-0.1332-0.0092-0.0081-0.01650.0087-0.00270.06820.0795-0.07910.589725.818810.5123-8.7932
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-2 - 45
2X-RAY DIFFRACTION2A46 - 156
3X-RAY DIFFRACTION3B3 - 56
4X-RAY DIFFRACTION4B57 - 156

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