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- PDB-9nid: Cryo-EM structure of the PI3K alpha/KRas/HER3 phosphopeptide comp... -

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Basic information

Entry
Database: PDB / ID: 9nid
TitleCryo-EM structure of the PI3K alpha/KRas/HER3 phosphopeptide complex dimer on POPC/POPS/PIP2 nanodiscs low-pass filtered to 5 angstroms
Components
  • Isoform 2B of GTPase KRas
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTransferase/Hydrolase / lipid kinase / GTPase / ONCOPROTEIN / Transferase-Hydrolase 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 / autosome genomic imprinting / Activated NTRK2 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 / autosome genomic imprinting / Activated NTRK2 signals through PI3K / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / phosphatidylinositol 3-kinase complex / TORC2 signaling / Co-stimulation by ICOS / Signaling by cytosolic FGFR1 fusion mutants / positive regulation of protein localization to membrane / vasculature development / regulation of cellular respiration / Nephrin family interactions / Signaling by LTK in cancer / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by LTK / anoikis / relaxation of cardiac muscle / phosphatidylinositol 3-kinase complex, class IA / PI3K/AKT activation / MET activates PI3K/AKT signaling / 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 / response to mineralocorticoid / GMP binding / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / forebrain astrocyte development / response to dexamethasone / LRR domain binding / PI-3K cascade:FGFR2 / negative regulation of macroautophagy / PI-3K cascade:FGFR4 / regulation of synaptic transmission, GABAergic / PI-3K cascade:FGFR1 / negative regulation of epithelial cell differentiation / response to isolation stress / phosphatidylinositol phosphate biosynthetic process / response to gravity / epithelial tube branching involved in lung morphogenesis / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / type I pneumocyte differentiation / Rac protein signal transduction / RET signaling / myoblast proliferation / negative regulation of anoikis / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / PI3K events in ERBB2 signaling / PI3K Cascade / intercalated disc / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / Role of LAT2/NTAL/LAB on calcium mobilization / skeletal muscle cell differentiation / positive regulation of glial cell proliferation / CD28 dependent PI3K/Akt signaling / RAC2 GTPase cycle / regulation of multicellular organism growth / Interleukin receptor SHC signaling / SOS-mediated signalling / Activated NTRK3 signals through RAS / Role of phospholipids in phagocytosis / Activated NTRK2 signals through RAS / adipose tissue development / positive regulation of TOR signaling / protein kinase activator activity / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / GAB1 signalosome / Signalling to RAS / endothelial cell migration / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / positive regulation of Rac protein signal transduction / phagocytosis / SHC-mediated cascade:FGFR3 / glial cell proliferation / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4
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 / Small GTPase, Ras-type / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / C2 domain superfamily / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase KRas / 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: 5 Å
AuthorsTorosyan, H. / Natalia, J. / Verba, K.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)U54CA274502 United States
CitationJournal: bioRxiv / Year: 2025
Title: Structures of the PI3Kα/KRas complex on lipid bilayers reveal the molecular mechanism of PI3Kα activation.
Authors: Hayarpi Torosyan / Michael D Paul / Allison Maker / Brigitte G Meyer / Natalia Jura / Kliment A Verba
Abstract: PI3Kα is a potent oncogene that converts PIP2 to PIP3 at the plasma membrane upon activation by receptor tyrosine kinases and Ras GTPases. In the absence of any structures of activated PI3Kα, the ...PI3Kα is a potent oncogene that converts PIP2 to PIP3 at the plasma membrane upon activation by receptor tyrosine kinases and Ras GTPases. In the absence of any structures of activated PI3Kα, the molecular details of its activation remain unknown. Here, we present cryo-EM structures of the PI3Kα/KRas complex embedded in lipid nanodiscs, revealing a rich ensemble of PI3Kα states adopted at the membrane surface. The sequential addition of a lipid bilayer, PIP2 and an activating phosphopeptide leads to the progressive release of key inhibitory domains from the PI3Kα catalytic core, which directly correlates with the reorganization of its active site. While association with POPC/POPS nanodiscs partially relieves PI3Kα autoinhibition, incorporation of PIP2 triggers near-complete displacement of PI3Kα inhibitory domains and significant restructuring of active site regulatory motifs. The addition of the activating phosphopeptide induces dimerization of the PI3Kα/KRas complex through a p110α catalytic subunit-mediated interface that is sterically occluded in autoinhibited PI3Kα. In cells, this dimeric PI3Kα complex amplifies Akt signaling in response to growth factor stimulation. Collectively, our structures map the conformational landscape of PI3Kα activation and reveal previously unexplored interfaces for potential therapeutic targeting.
History
DepositionFeb 26, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 13, 2026Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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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
B: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
C: Isoform 2B of GTPase KRas
D: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)300,82110
Polymers298,5644
Non-polymers2,2566
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 / 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: 127822.578 Da / Num. of mol.: 2
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: Protein Isoform 2B of GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 21459.605 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P01116, small monomeric GTPase
#3: Chemical ChemComp-A1AZD / tert-butyl [2-(2-{[(2P)-2-{4-[4-(2-amino-2-oxoethyl)-2-fluoroanilino]thieno[2,3-d]pyridazin-7-yl}phenyl]oxy}ethoxy)ethyl]carbamate


Mass: 581.658 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H32FN5O5S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O13P3 / Feature type: SUBJECT OF INVESTIGATION
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
Has ligand of interestY
Has protein modificationN

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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: full-length p85 alpha and p110 alpha heterodimer/KRas/HER3 phosphopeptide complex dimer bound to POPC/POPS/PIP2-MSP1E3D1 nanodiscs
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.465218 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5 / Details: 50 mM Tris-HCL, 150 mM NaCl, 1mM TCEP
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 5 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 47.7 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.3.1particle selection
4cryoSPARC4.3.1CTF correction
7UCSF ChimeraX1.7.1model fitting
8Rosetta3model fitting
10Coot8model refinement
11ISOLDEmodel refinement
12cryoSPARC4.3.1initial Euler assignment
13cryoSPARC4.3.1final Euler assignment
15cryoSPARC4.3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6259852
3D reconstructionResolution: 5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 280864 / Symmetry type: POINT

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