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- PDB-6ykg: Structure-based exploration of selectivity for ATM inhibitors in ... -

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Basic information

Entry
Database: PDB / ID: 6ykg
TitleStructure-based exploration of selectivity for ATM inhibitors in Huntingtons disease
ComponentsPhosphatidylinositol 3-kinase catalytic subunit type 3
KeywordsLYASE / Huntingtons disease / VPS34 / ATM
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 assembly / autophagosome maturation / 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-OZ8 / Phosphatidylinositol 3-kinase catalytic subunit type 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.12 Å
AuthorsVan de Poel, A. / Leonard, P.M. / Lamers, M.B.A.C.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease.
Authors: Van de Poel, A. / Toledo-Sherman, L. / Breccia, P. / Cachope, R. / Bate, J.R. / Angulo-Herrera, I. / Wishart, G. / Matthews, K.L. / Martin, S.L. / Peacock, M. / Barnard, A. / Cox, H.C. / ...Authors: Van de Poel, A. / Toledo-Sherman, L. / Breccia, P. / Cachope, R. / Bate, J.R. / Angulo-Herrera, I. / Wishart, G. / Matthews, K.L. / Martin, S.L. / Peacock, M. / Barnard, A. / Cox, H.C. / Jones, G. / McAllister, G. / Vater, H. / Esmieu, W. / Clissold, C. / Lamers, M. / Leonard, P. / Jarvis, R.E. / Blackaby, W. / Eznarriaga, M. / Lazari, O. / Yates, D. / Rose, M. / Jang, S.W. / Munoz-Sanjuan, I. / Dominguez, C.
History
DepositionApr 6, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _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
AAA: Phosphatidylinositol 3-kinase catalytic subunit type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,9322
Polymers72,5931
Non-polymers3391
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area24010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.864, 168.115, 61.692
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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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: 72592.781 Da / Num. of mol.: 1
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-OZ8 / 4-morpholin-4-yl-6-[(2~{R})-2-(phenylmethyl)pyrrolidin-1-yl]-1~{H}-pyridin-2-one


Mass: 339.431 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H25N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.85 Å3/Da / Density % sol: 56.88 %
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

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Mar 24, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 3.12→49.73 Å / Num. obs: 15383 / % possible obs: 99.8 % / Redundancy: 3 % / CC1/2: 0.999 / Net I/σ(I): 9
Reflection shellResolution: 3.12→3.34 Å / Num. unique obs: 2732 / CC1/2: 0.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6I3U

6i3u


Resolution: 3.12→49.73 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.896 / Cross valid method: FREE R-VALUE / ESU R Free: 0.46
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2609 815 5.298 %
Rwork0.2147 --
all0.217 --
obs-15383 99.676 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 56.468 Å2
Baniso -1Baniso -2Baniso -3
1-7.539 Å20 Å20 Å2
2---1.223 Å20 Å2
3----6.316 Å2
Refinement stepCycle: LAST / Resolution: 3.12→49.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4442 0 25 1 4468
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0134558
X-RAY DIFFRACTIONr_bond_other_d0.0350.0174240
X-RAY DIFFRACTIONr_angle_refined_deg1.8511.6456177
X-RAY DIFFRACTIONr_angle_other_deg2.2881.5799843
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4475556
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.42922.845239
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.78815805
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4031528
X-RAY DIFFRACTIONr_chiral_restr0.1230.2589
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025046
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02918
X-RAY DIFFRACTIONr_nbd_refined0.1780.2939
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1810.23921
X-RAY DIFFRACTIONr_nbtor_refined0.1610.22206
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0680.22250
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0960.274
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1060.212
X-RAY DIFFRACTIONr_nbd_other0.1610.246
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2940.22
X-RAY DIFFRACTIONr_mcbond_it2.3986.1142233
X-RAY DIFFRACTIONr_mcbond_other2.3946.1142232
X-RAY DIFFRACTIONr_mcangle_it4.1389.1652786
X-RAY DIFFRACTIONr_mcangle_other4.1389.1652787
X-RAY DIFFRACTIONr_scbond_it2.3156.2892325
X-RAY DIFFRACTIONr_scbond_other2.3146.2882326
X-RAY DIFFRACTIONr_scangle_it4.1119.353391
X-RAY DIFFRACTIONr_scangle_other4.1119.3493392
X-RAY DIFFRACTIONr_lrange_it6.57270.1264972
X-RAY DIFFRACTIONr_lrange_other6.57270.1184973
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.12-3.2010.386630.381053X-RAY DIFFRACTION99.554
3.201-3.2890.356520.3461029X-RAY DIFFRACTION100
3.289-3.3840.377670.299988X-RAY DIFFRACTION99.7164
3.384-3.4880.327500.275979X-RAY DIFFRACTION99.6128
3.488-3.6020.279600.248950X-RAY DIFFRACTION99.5074
3.602-3.7290.316480.248902X-RAY DIFFRACTION99.5807
3.729-3.8690.263570.223887X-RAY DIFFRACTION99.5781
3.869-4.0270.258430.208846X-RAY DIFFRACTION99.8876
4.027-4.2060.242410.178836X-RAY DIFFRACTION99.3205
4.206-4.4110.228290.175796X-RAY DIFFRACTION100
4.411-4.650.236410.162749X-RAY DIFFRACTION100
4.65-4.9320.222440.164701X-RAY DIFFRACTION99.7323
4.932-5.2720.244420.167681X-RAY DIFFRACTION100
5.272-5.6940.239370.191632X-RAY DIFFRACTION100
5.694-6.2360.252300.197589X-RAY DIFFRACTION99.8387
6.236-6.9710.312250.202537X-RAY DIFFRACTION100
6.971-8.0470.209280.155476X-RAY DIFFRACTION100
8.047-9.850.17240.125412X-RAY DIFFRACTION99.7712
9.85-13.9070.171240.144325X-RAY DIFFRACTION99.7143
13.907-49.730.24100.444200X-RAY DIFFRACTION97.6744

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