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- PDB-9xw5: Cryo-EM structure of PI3Kalpha H1047R mutation in complex with STX-478 -

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Basic information

Entry
Database: PDB / ID: 9xw5
TitleCryo-EM structure of PI3Kalpha H1047R mutation in complex with STX-478
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 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


perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / 1-phosphatidylinositol-3-kinase regulator activity / T follicular helper cell differentiation / phosphatidylinositol 3-kinase activator activity / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol kinase activity / regulation of actin filament organization / phosphatidylinositol 3-kinase regulator activity ...perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / 1-phosphatidylinositol-3-kinase regulator activity / T follicular helper cell differentiation / phosphatidylinositol 3-kinase activator activity / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol kinase activity / regulation of actin filament organization / phosphatidylinositol 3-kinase regulator activity / response to butyrate / negative regulation of actin filament depolymerization / IRS-mediated signalling / phosphatidylinositol 3-kinase regulatory subunit binding / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / neurotrophin TRKA receptor binding / positive regulation of focal adhesion disassembly / response to L-leucine / cellular response to hydrostatic pressure / cis-Golgi network / Activated NTRK2 signals through PI3K / transmembrane receptor protein tyrosine kinase adaptor activity / ErbB-3 class receptor binding / negative regulation of stress fiber assembly / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / phosphatidylinositol 3-kinase complex / Co-stimulation by ICOS / TORC2 signaling / positive regulation of protein localization to membrane / Signaling by cytosolic FGFR1 fusion mutants / RHOD GTPase cycle / vasculature development / positive regulation of filopodium assembly / Nephrin family interactions / RHOF GTPase cycle / Signaling by LTK in cancer / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by LTK / kinase activator activity / anoikis / RND1 GTPase cycle / RND2 GTPase cycle / phosphatidylinositol 3-kinase complex, class IA / MET activates PI3K/AKT signaling / RND3 GTPase cycle / PI3K/AKT activation / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / growth hormone receptor signaling pathway / relaxation of cardiac muscle / natural killer cell mediated cytotoxicity / insulin binding / phosphatidylinositol 3-kinase / Signaling by ALK / phosphatidylinositol-3-phosphate biosynthetic process / cardiac muscle cell contraction / RHOV GTPase cycle / RHOB GTPase cycle / vascular endothelial growth factor signaling pathway / GP1b-IX-V activation signalling / 1-phosphatidylinositol-3-kinase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / response to dexamethasone / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / positive regulation of protein kinase activity / RHOU GTPase cycle / response to muscle stretch / phosphatidylinositol-mediated signaling / RET signaling / CDC42 GTPase cycle / T cell differentiation / negative regulation of anoikis / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K events in ERBB2 signaling / RHOG GTPase cycle / insulin receptor substrate binding / PI3K Cascade / Role of LAT2/NTAL/LAB on calcium mobilization / RAC3 GTPase cycle / RHOA GTPase cycle / RAC2 GTPase cycle / Interleukin receptor SHC signaling / intercalated disc / Role of phospholipids in phagocytosis / CD28 dependent PI3K/Akt signaling / GAB1 signalosome / endothelial cell migration / enzyme-substrate adaptor activity / substrate adhesion-dependent cell spreading / protein kinase activator activity / negative regulation of macroautophagy
Similarity search - Function
Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain ...Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / 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. / Rho GTPase activation protein / 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 / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-ZWE / Phosphatidylinositol 3-kinase regulatory subunit alpha / 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: 3.31 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)82073904 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 mutants by RLY-2608 and STX-478.
Authors: Xiao Liu / Yanyan Chen / Guanyi Li / Anqi Chen / Qingtong Zhou / Ming-Wei Wang /
Abstract: Hotspot mutations in phosphoinositide 3-kinase alpha (PI3K), such as H1047R, E542K, and E545K, drive tumorigenesis across multiple cancer types. Orthosteric PI3K inhibitors are effective but have ...Hotspot mutations in phosphoinositide 3-kinase alpha (PI3K), such as H1047R, E542K, and E545K, drive tumorigenesis across multiple cancer types. Orthosteric PI3K inhibitors are effective but have toxicity against wild-type PI3K, the emergence of resistance, and a narrow therapeutic index. Allosteric inhibitors such as RLY-2608 and STX-478 offer a promising path toward mutant-specific suppression, yet the structural basis for their selectivity and mechanisms of action remain elusive. Here, we report high-resolution cryogenic electron microscopy structures of RLY-2608- and STX-478-bound H1047R, E542K, and E545K, revealing a shared cryptic allosteric pocket, accessible only through a major conformational rearrangement of the activation loop that is stabilized in oncogenic mutants. While both inhibitors occupy this pocket, they have distinct interaction networks and propagate divergent allosteric activities: RLY-2608 induces large-scale remodeling of catalytic and membrane-interacting elements, whereas STX-478 reinforces autoinhibitory interfaces between p110 and p85 subunits. Comparative analysis provides structural insights into their differentiated potency and selectivity.
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
Revision 1.1Oct 7, 2026Group: Data collection / Database references / Category: citation / em_admin
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Revision 1.1Oct 7, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin
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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
B: Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)211,8663
Polymers211,4652
Non-polymers4011
Water00
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: 127841.625 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: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha / PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory ...PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PI3-kinase subunit p85-alpha / PtdIns-3-kinase regulatory subunit p85-alpha


Mass: 83623.203 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P27986
#3: 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
Has ligand of interestY
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 H1047R in complex with STX-478 / Type: COMPLEX / Entity ID: #1-#2 / 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: BRIGHT FIELD / 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
13cryoSPARC4.5.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 5684108 / Symmetry type: POINT

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