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- PDB-6i3u: Optimization of potent and selective ATM inhibitors suitable for ... -

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Basic information

Entry
Database: PDB / ID: 6i3u
TitleOptimization of potent and selective ATM inhibitors suitable for a proof-of-concept study in Huntington's disease models
ComponentsPhosphatidylinositol 3-kinase catalytic subunit type 3
KeywordsLYASE / ATM surrogate / VPS34 / Kinase / Huntington's disease
Function / homology
Function and homology information


Toll Like Receptor 9 (TLR9) Cascade / protein lipidation / Synthesis of PIPs at the late endosome membrane / phosphatidylinositol 3-kinase complex, class III / Synthesis of PIPs at the early endosome membrane / phosphatidylinositol 3-kinase complex, class III, type II / phosphatidylinositol 3-kinase complex, class III, type I / autophagy of peroxisome / positive regulation by host of viral genome replication / Synthesis of PIPs at the Golgi membrane ...Toll Like Receptor 9 (TLR9) Cascade / protein lipidation / Synthesis of PIPs at the late endosome membrane / phosphatidylinositol 3-kinase complex, class III / Synthesis of PIPs at the early endosome membrane / phosphatidylinositol 3-kinase complex, class III, type II / phosphatidylinositol 3-kinase complex, class III, type I / autophagy of peroxisome / positive regulation by host of viral genome replication / Synthesis of PIPs at the Golgi membrane / phosphatidylinositol kinase activity / protein localization to phagophore assembly site / protein targeting to lysosome / early endosome to late endosome transport / phagophore assembly site / Translation of Replicase and Assembly of the Replication Transcription Complex / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Macroautophagy / autolysosome / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / axoneme / PI3K Cascade / autophagosome maturation / autophagosome assembly / RHO GTPases Activate NADPH Oxidases / regulation of macroautophagy / cellular response to glucose starvation / autophagosome / regulation of cytokinesis / regulation of autophagy / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / macroautophagy / autophagy / endocytosis / phagocytic vesicle membrane / late endosome / peroxisome / kinase activity / Translation of Replicase and Assembly of the Replication Transcription Complex / midbody / protein kinase activity / endosome / cell division / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP binding / membrane / cytosol / cytoplasm
Similarity search - Function
Phosphatidylinositol 3-kinase, Vps34 type / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase ...Phosphatidylinositol 3-kinase, Vps34 type / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / C2 domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-H2E / Phosphatidylinositol 3-kinase catalytic subunit type 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09 Å
AuthorsLeonard, P.M.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models.
Authors: Toledo-Sherman, L. / Breccia, P. / Cachope, R. / Bate, J.R. / Angulo-Herrera, I. / Wishart, G. / Matthews, K.L. / Martin, S.L. / Cox, H.C. / McAllister, G. / Penrose, S.D. / Vater, H. / ...Authors: Toledo-Sherman, L. / Breccia, P. / Cachope, R. / Bate, J.R. / Angulo-Herrera, I. / Wishart, G. / Matthews, K.L. / Martin, S.L. / Cox, H.C. / McAllister, G. / Penrose, S.D. / Vater, H. / Esmieu, W. / Van de Poel, A. / Van de Bospoort, R. / Strijbosch, A. / Lamers, M. / Leonard, P. / Jarvis, R.E. / Blackaby, W. / Barnes, K. / Eznarriaga, M. / Dowler, S. / Smith, G.D. / Fischer, D.F. / Lazari, O. / Yates, D. / Rose, M. / Jang, S.W. / Munoz-Sanjuan, I. / Dominguez, C.
History
DepositionNov 7, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 20, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Apr 10, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jan 24, 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: Phosphatidylinositol 3-kinase catalytic subunit type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,6422
Polymers70,1211
Non-polymers5211
Water3,225179
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area23970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.170, 167.170, 61.500
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-1175-

HOH

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Components

#1: Protein Phosphatidylinositol 3-kinase catalytic subunit type 3 / PtdIns-3-kinase type 3 / Phosphatidylinositol 3-kinase p100 subunit / Phosphoinositide-3-kinase ...PtdIns-3-kinase type 3 / Phosphatidylinositol 3-kinase p100 subunit / Phosphoinositide-3-kinase class 3 / hVps34


Mass: 70121.102 Da / Num. of mol.: 1 / Mutation: F612A, L616N, I634L, M682L, F684W, Q686_S687insG
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3C3, VPS34 / Production host: Escherichia coli (E. coli) / References: UniProt: Q8NEB9, phosphatidylinositol 3-kinase
#2: Chemical ChemComp-H2E / 2-morpholin-4-yl-6-[7-[(2~{R})-1-morpholin-4-ylpropan-2-yl]oxy-9~{H}-thioxanthen-4-yl]pyran-4-one


Mass: 520.640 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H32N2O5S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 179 / 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: 3.09 Å3/Da / Density % sol: 60.13 % / Description: Rod-like crystals
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 1.4 M Sodium Malonate pH 7.0, 0.1 M Bis-Tris Propane pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 9, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.09→83.58 Å / Num. obs: 51984 / % possible obs: 99.5 % / Redundancy: 6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.084 / Rpim(I) all: 0.037 / Rrim(I) all: 0.093 / Net I/σ(I): 12.8
Reflection shellResolution: 2.09→2.13 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.82 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 2465 / CC1/2: 0.645 / Rpim(I) all: 0.521 / Rrim(I) all: 0.978 / % possible all: 95.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LS8

3ls8


Resolution: 2.09→83.58 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.947 / SU B: 6.067 / SU ML: 0.145 / Cross valid method: THROUGHOUT / ESU R: 0.156 / ESU R Free: 0.154 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23556 2561 4.9 %RANDOM
Rwork0.18869 ---
obs0.19096 49365 99.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 42.587 Å2
Baniso -1Baniso -2Baniso -3
1-4.09 Å20 Å20 Å2
2---0.21 Å20 Å2
3----3.87 Å2
Refinement stepCycle: 1 / Resolution: 2.09→83.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4418 0 37 179 4634
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0134547
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174218
X-RAY DIFFRACTIONr_angle_refined_deg1.4471.6426169
X-RAY DIFFRACTIONr_angle_other_deg1.3061.5689792
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0315554
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.46422.996237
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.00815796
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.1561526
X-RAY DIFFRACTIONr_chiral_restr0.0730.2587
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025025
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02904
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_it3.0574.412225
X-RAY DIFFRACTIONr_mcbond_other3.0544.4092224
X-RAY DIFFRACTIONr_mcangle_it4.4336.612776
X-RAY DIFFRACTIONr_mcangle_other4.4336.6112777
X-RAY DIFFRACTIONr_scbond_it4.0134.8242322
X-RAY DIFFRACTIONr_scbond_other4.0124.8232323
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.1847.0553394
X-RAY DIFFRACTIONr_long_range_B_refined7.59151.635101
X-RAY DIFFRACTIONr_long_range_B_other7.59551.5295072
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.09→2.144 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.342 174 -
Rwork0.342 3470 -
obs--95.92 %

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