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- PDB-6oac: PQR530 [(S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpho... -

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Basic information

Entry
Database: PDB / ID: 6oac
TitlePQR530 [(S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine] bound to the PI3Ka catalytic subunit p110alpha
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE / PIK3CA / mTOR / phosphoinositide / PIP3 / PI3K / p110 / SIGNALING PROTEIN
Function / homology
Function and homology information


response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / autosome genomic imprinting / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure ...response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / autosome genomic imprinting / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / regulation of cellular respiration / positive regulation of protein localization to membrane / Activated NTRK2 signals through PI3K / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / vasculature development / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by cytosolic FGFR1 fusion mutants / Co-stimulation by ICOS / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / Nephrin family interactions / anoikis / Signaling by LTK in cancer / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by LTK / MET activates PI3K/AKT signaling / PI3K/AKT activation / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / vascular endothelial growth factor signaling pathway / relaxation of cardiac muscle / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of macroautophagy / PI-3K cascade:FGFR2 / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / response to dexamethasone / negative regulation of anoikis / RET signaling / PI3K events in ERBB2 signaling / protein kinase activator activity / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / regulation of multicellular organism growth / intercalated disc / CD28 dependent PI3K/Akt signaling / positive regulation of TOR signaling / RAC2 GTPase cycle / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / GAB1 signalosome / Role of phospholipids in phagocytosis / adipose tissue development / phagocytosis / endothelial cell migration / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Signaling by FGFR4 in disease / positive regulation of lamellipodium assembly / energy homeostasis / Signaling by FLT3 ITD and TKD mutants / cardiac muscle contraction / GPVI-mediated activation cascade / Signaling by FGFR3 in disease / Tie2 Signaling / Signaling by FGFR2 in disease / response to muscle stretch / T cell costimulation / RAC1 GTPase cycle / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Downstream signal transduction / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / liver development / response to activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Regulation of signaling by CBL / positive regulation of smooth muscle cell proliferation / cellular response to glucose stimulus / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / platelet activation / VEGFA-VEGFR2 Pathway / epidermal growth factor receptor signaling pathway / cellular response to insulin stimulus / glucose metabolic process
Similarity search - Function
PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain / PI3-kinase family, ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. ...PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain / PI3-kinase family, ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. / 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. / C2 domain / 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 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-M1J / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.15 Å
AuthorsBurke, J.E. / McPhail, J.A.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)142393 Canada
CitationJournal: J.Med.Chem. / Year: 2019
Title: (S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.
Authors: Rageot, D. / Bohnacker, T. / Keles, E. / McPhail, J.A. / Hoffmann, R.M. / Melone, A. / Borsari, C. / Sriramaratnam, R. / Sele, A.M. / Beaufils, F. / Hebeisen, P. / Fabbro, D. / Hillmann, P. ...Authors: Rageot, D. / Bohnacker, T. / Keles, E. / McPhail, J.A. / Hoffmann, R.M. / Melone, A. / Borsari, C. / Sriramaratnam, R. / Sele, A.M. / Beaufils, F. / Hebeisen, P. / Fabbro, D. / Hillmann, P. / Burke, J.E. / Wymann, M.P.
History
DepositionMar 15, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 26, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jul 24, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 11, 2023Group: 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 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,6072
Polymers110,1991
Non-polymers4071
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.926, 135.511, 144.498
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / p110alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 110199.398 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P42336, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-M1J / 4-(difluoromethyl)-5-{4-[(3S)-3-methylmorpholin-4-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-yl}pyridin-2-amine


Mass: 407.418 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H23F2N7O2 / Feature type: SUBJECT OF INVESTIGATION

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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: 2.62 Å3/Da / Density % sol: 53.01 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 9.5
Details: 8% PEG6000, 0.6M Na Formate, 0.1M CHES pH 9.5, 5mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 0.97 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jun 26, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 3.15→39.26 Å / Num. obs: 20690 / % possible obs: 99.5 % / Redundancy: 8.3 % / Biso Wilson estimate: 101.78 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.153 / Rpim(I) all: 0.056 / Rrim(I) all: 0.163 / Net I/σ(I): 9.1
Reflection shellResolution: 3.15→3.36 Å / Redundancy: 8.5 % / Rmerge(I) obs: 2.096 / Num. unique obs: 3642 / CC1/2: 0.603 / Rpim(I) all: 0.756 / Rrim(I) all: 2.231 / % possible all: 98.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
Aimless0.7.1data scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4TUU

4tuu


Resolution: 3.15→39.257 Å / SU ML: 0.58 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 35.5
RfactorNum. reflection% reflection
Rfree0.2872 1033 5.03 %
Rwork0.2425 --
obs0.2449 20524 99.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 271.35 Å2 / Biso mean: 121.8135 Å2 / Biso min: 55.91 Å2
Refinement stepCycle: final / Resolution: 3.15→39.257 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6356 0 52 0 6408
Biso mean--136.34 --
Num. residues----847
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0026534
X-RAY DIFFRACTIONf_angle_d0.4158916
X-RAY DIFFRACTIONf_chiral_restr0.0371018
X-RAY DIFFRACTIONf_plane_restr0.0031145
X-RAY DIFFRACTIONf_dihedral_angle_d8.9253871
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.1496-3.31550.45761410.43542672281397
3.3155-3.52320.31441530.324427332886100
3.5232-3.7950.33381400.275427672907100
3.795-4.17650.3121500.2322733288398
4.1765-4.77990.26631450.209628052950100
4.7799-6.01870.29531460.224628583004100
6.0187-39.26050.2451580.22242923308199
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)
14.5419-1.5223-2.61472.59990.49444.2217-0.4273-0.2537-0.62760.16590.24110.31890.74770.38550.26680.86940.07980.04560.7840.05851.500514.9361-9.650833.3268
21.2220.0729-0.88615.41021.60031.679-0.09150.12680.0781-0.01180.2391-0.4391-0.11940.2707-0.20010.6348-0.1106-0.03710.67530.01361.123510.807521.25736.9412
30.28940.292-0.29510.6502-1.35274.195-0.63520.8942-1.036-0.53841.1368-1.12520.9647-0.9495-0.42931.5967-0.29290.53280.9739-0.36341.33585.7333-23.32190.4654
44.12871.8864-1.58056.79881.19464.7247-0.39940.56120.2871-0.35630.4298-0.70930.3084-0.2871-0.02910.8084-0.2310.13710.7317-0.04031.10213.6115-19.54359.21
52.80880.0159-0.02044.05560.11783.2695-0.40260.8492-0.3648-1.19130.2944-0.9528-0.15680.45890.08270.9754-0.3660.30481.0437-0.24551.123916.11582.56663.8238
64.43620.229-1.32771.95980.35761.6175-0.0548-0.3116-0.37090.2154-0.05710.14760.1793-0.24410.12040.6278-0.07380.04230.62390.0121.0141-5.17191.972336.6983
73.7457-0.8617-0.93495.2831-1.78543.5148-0.08530.60870.5522-0.31780.48450.8899-0.3342-0.7449-0.3770.8148-0.0281-0.11440.84850.05491.0115-15.557419.870921.1838
83.7333-0.22470.20457.0848-0.63344.1653-0.68610.92930.4477-1.32970.43060.0075-0.8464-1.26350.15291.2286-0.0177-0.31561.3214-0.04410.7533-7.407115.8785.8811
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 107 through 156 )A107 - 156
2X-RAY DIFFRACTION2chain 'A' and (resid 157 through 334 )A157 - 334
3X-RAY DIFFRACTION3chain 'A' and (resid 335 through 399 )A335 - 399
4X-RAY DIFFRACTION4chain 'A' and (resid 400 through 477 )A400 - 477
5X-RAY DIFFRACTION5chain 'A' and (resid 478 through 647 )A478 - 647
6X-RAY DIFFRACTION6chain 'A' and (resid 648 through 807 )A648 - 807
7X-RAY DIFFRACTION7chain 'A' and (resid 808 through 974 )A808 - 974
8X-RAY DIFFRACTION8chain 'A' and (resid 975 through 1046 )A975 - 1046

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