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- PDB-6pys: Human PI3Kalpha in complex with Compound 2-10 ((3S)-3-benzyl-3-me... -

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Basic information

Entry
Database: PDB / ID: 6pys
TitleHuman PI3Kalpha in complex with Compound 2-10 ((3S)-3-benzyl-3-methyl-5-[5-(2-methylpyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-1,3-dihydro-2H-indol-2-one)
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PI3Kalpha kinase / transferase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


response to muscle inactivity / regulation of actin filament organization / negative regulation of actin filament depolymerization / response to butyrate / IRS-mediated signalling / response to L-leucine / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / Activated NTRK2 signals through PI3K / Activated NTRK3 signals through PI3K ...response to muscle inactivity / regulation of actin filament organization / negative regulation of actin filament depolymerization / response to butyrate / IRS-mediated signalling / response to L-leucine / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / Activated NTRK2 signals through PI3K / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / phosphatidylinositol 3-kinase complex / TORC2 signaling / Co-stimulation by ICOS / positive regulation of protein localization to membrane / Signaling by cytosolic FGFR1 fusion mutants / vasculature development / Nephrin family interactions / Signaling by LTK in cancer / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by LTK / anoikis / phosphatidylinositol 3-kinase complex, class IA / MET activates PI3K/AKT signaling / PI3K/AKT activation / relaxation of cardiac muscle / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by ALK / cardiac muscle cell contraction / 1-phosphatidylinositol-3-kinase activity / vascular endothelial growth factor signaling pathway / negative regulation of macroautophagy / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / response to dexamethasone / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / positive regulation of protein kinase activity / PI-3K cascade:FGFR1 / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / RET signaling / negative regulation of anoikis / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K events in ERBB2 signaling / insulin receptor substrate binding / intercalated disc / PI3K Cascade / Role of LAT2/NTAL/LAB on calcium mobilization / CD28 dependent PI3K/Akt signaling / RAC2 GTPase cycle / Interleukin receptor SHC signaling / positive regulation of TOR signaling / Role of phospholipids in phagocytosis / GAB1 signalosome / protein kinase activator activity / endothelial cell migration / phagocytosis / GPVI-mediated activation cascade / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / positive regulation of lamellipodium assembly / Signaling by FGFR4 in disease / Signaling by FLT3 ITD and TKD mutants / response to muscle stretch / cardiac muscle contraction / Signaling by FGFR3 in disease / RAC1 GTPase cycle / Tie2 Signaling / Signaling by FGFR2 in disease / insulin-like growth factor receptor signaling pathway / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / positive regulation of smooth muscle cell proliferation / Downstream signal transduction / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / response to activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Regulation of signaling by CBL / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / platelet activation / Signaling by ERBB2 KD Mutants / VEGFA-VEGFR2 Pathway / epidermal growth factor receptor signaling pathway / cellular response to insulin stimulus / Constitutive Signaling by Aberrant PI3K in Cancer / Signaling by CSF1 (M-CSF) in myeloid cells / insulin receptor signaling pathway / Signaling by ALK fusions and activated point mutants / DAP12 signaling / PIP3 activates AKT signaling / T cell receptor signaling pathway / Downstream TCR signaling
Similarity search - Function
PI3Kalpha, catalytic domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / 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 ...PI3Kalpha, catalytic domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / 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 domain / 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 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-P5J / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.19 Å
AuthorsLesburg, C.A. / Augustin, M.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Design of selective PI3K delta inhibitors using an iterative scaffold-hopping workflow.
Authors: Fradera, X. / Methot, J.L. / Achab, A. / Christopher, M. / Altman, M.D. / Zhou, H. / McGowan, M.A. / Kattar, S.D. / Wilson, K. / Garcia, Y. / Augustin, M.A. / Lesburg, C.A. / Shah, S. / ...Authors: Fradera, X. / Methot, J.L. / Achab, A. / Christopher, M. / Altman, M.D. / Zhou, H. / McGowan, M.A. / Kattar, S.D. / Wilson, K. / Garcia, Y. / Augustin, M.A. / Lesburg, C.A. / Shah, S. / Goldenblatt, P. / Katz, J.D.
History
DepositionJul 30, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 13, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)110,6144
Polymers109,9831
Non-polymers6313
Water2,918162
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area520 Å2
ΔGint-1 kcal/mol
Surface area39900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.440, 133.914, 141.719
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: 109983.094 Da / Num. of mol.: 1 / Fragment: UNP residues 107-1051
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-P5J / (3S)-3-benzyl-3-methyl-5-[5-(2-methylpyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-1,3-dihydro-2H-indol-2-one


Mass: 446.503 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H22N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 162 / 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: 2.61 Å3/Da / Density % sol: 52.87 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: not available

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 14, 2014
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.19→97.33 Å / Num. obs: 57664 / % possible obs: 99.2 % / Redundancy: 4.7 % / Biso Wilson estimate: 56.064 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.054 / Rrim(I) all: 0.061 / Χ2: 0.976 / Net I/σ(I): 16.58
Reflection shellResolution: 2.19→2.44 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.594 / Mean I/σ(I) obs: 3.32 / Num. unique obs: 15711 / CC1/2: 0.995 / Rrim(I) all: 0.042 / % possible all: 99

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.19→97.33 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.932 / SU B: 7.108 / SU ML: 0.176 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.258 / ESU R Free: 0.207
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2591 1498 2.6 %RANDOM
Rwork0.2239 ---
obs0.2248 56166 99.24 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 125.15 Å2 / Biso mean: 57.165 Å2 / Biso min: 19.63 Å2
Baniso -1Baniso -2Baniso -3
1-0.49 Å20 Å2-0 Å2
2--2.38 Å2-0 Å2
3----2.87 Å2
Refinement stepCycle: final / Resolution: 2.19→97.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7277 0 45 166 7488
Biso mean--63.61 52.87 -
Num. residues----890
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0197291
X-RAY DIFFRACTIONr_bond_other_d0.0020.026861
X-RAY DIFFRACTIONr_angle_refined_deg1.0521.9639903
X-RAY DIFFRACTIONr_angle_other_deg0.879315686
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9125894
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.4324.177328
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.832151222
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0171540
X-RAY DIFFRACTIONr_chiral_restr0.0580.21100
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0218249
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021699
LS refinement shellResolution: 2.19→2.247 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.35 109 -
Rwork0.326 4084 -
all-4193 -
obs--98.71 %

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