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- PDB-9xw7: Cryo-EM structure of PI3Kalpha E545K mutation in complex with STX-478 -

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Basic information

Entry
Database: PDB / ID: 9xw7
TitleCryo-EM structure of PI3Kalpha E545K mutation in complex with STX-478
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsSTRUCTURAL PROTEIN / Phosphoinositide 3-kinase / drug target / ligand / binding pocket / hotspot mutation / allosteric inhbitor
Function / homology
Function and homology information


response to muscle inactivity / regulation of actin filament organization / response to butyrate / negative regulation of actin filament depolymerization / IRS-mediated signalling / PI3K events in ERBB4 signaling / response to L-leucine / cellular response to hydrostatic pressure / Activated NTRK2 signals through PI3K / Activated NTRK3 signals through PI3K ...response to muscle inactivity / regulation of actin filament organization / response to butyrate / negative regulation of actin filament depolymerization / IRS-mediated signalling / PI3K events in ERBB4 signaling / response to L-leucine / 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 / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / relaxation of cardiac muscle / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by ALK / cardiac muscle cell contraction / vascular endothelial growth factor signaling pathway / 1-phosphatidylinositol-3-kinase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / negative regulation of macroautophagy / response to dexamethasone / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / positive regulation of protein kinase activity / response to muscle stretch / 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 / PI3K Cascade / Role of LAT2/NTAL/LAB on calcium mobilization / RAC2 GTPase cycle / Interleukin receptor SHC signaling / intercalated disc / Role of phospholipids in phagocytosis / CD28 dependent PI3K/Akt signaling / positive regulation of TOR signaling / GAB1 signalosome / endothelial cell migration / protein kinase activator activity / positive regulation of lamellipodium assembly / cardiac muscle contraction / GPVI-mediated activation cascade / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / insulin-like growth factor receptor signaling pathway / Signaling by FGFR4 in disease / Signaling by FLT3 ITD and TKD mutants / RAC1 GTPase cycle / Signaling by FGFR3 in disease / Tie2 Signaling / Signaling by FGFR2 in disease / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / positive regulation of smooth muscle cell proliferation / Downstream signal transduction / response to activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Regulation of signaling by CBL / platelet activation / Constitutive Signaling by EGFRvIII / Signaling by SCF-KIT / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / VEGFA-VEGFR2 Pathway / insulin receptor signaling pathway / T cell receptor signaling pathway / epidermal growth factor receptor signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / Signaling by CSF1 (M-CSF) in myeloid cells / actin cytoskeleton organization / cellular response to insulin stimulus / Signaling by ALK fusions and activated point mutants / DAP12 signaling / PIP3 activates AKT signaling / cell migration
Similarity search - Function
PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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 ...PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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. / 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 / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-ZWE / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsLiu, X. / Chen, Y. / Li, G. / Chen, A. / Zhou, Q. / Wang, M.-W.
Funding support China, 5items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82273961 China
National Natural Science Foundation of China (NSFC) China
National Natural Science Foundation of China (NSFC)81872915 China
Other government China
Other government China
CitationJournal: Acta Pharm Sin B / Year: 2026
Title: Molecular architecture responsible for specific inhibition of oncogenic PI3K alpha mutants by RLY-2608 and STX-478
Authors: Liu, X. / Chen, Y. / Li, G. / Chen, A. / Zhou, Q. / Wang, M.W.
History
DepositionNov 27, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Sep 23, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 23, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

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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)128,2242
Polymers127,8231
Non-polymers4011
Water362
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform / PI3-kinase subunit alpha / PI3K-alpha / PI3Kalpha / PtdIns-3-kinase subunit alpha / ...PI3-kinase subunit alpha / PI3K-alpha / PI3Kalpha / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / PtdIns-3-kinase subunit p110-alpha / p110alpha / Phosphoinositide 3-kinase alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 127822.641 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P42336, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-ZWE / N-(2-aminopyrimidin-5-yl)-N'-[(1R)-1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]urea


Mass: 401.291 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H12F5N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human PI3Kalpha E542K in complex with STX-478 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.6
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: DIFFRACTION / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.5.1particle selection
2PHENIX1.20.1_4487model refinement
13cryoSPARC4.5.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 4873921 / Symmetry type: POINT
RefinementHighest resolution: 3.01 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0046989
ELECTRON MICROSCOPYf_angle_d0.7169444
ELECTRON MICROSCOPYf_dihedral_angle_d4.629901
ELECTRON MICROSCOPYf_chiral_restr0.0431029
ELECTRON MICROSCOPYf_plane_restr0.0081204

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