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- EMDB-49455: Cryo-EM structure of the Class 3 PI3K alpha/KRas complex on POPC/... -

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Entry
Database: EMDB / ID: EMD-49455
TitleCryo-EM structure of the Class 3 PI3K alpha/KRas complex on POPC/POPS nanodiscs
Map datastructure of the Class 3 PI3K alpha/KRas complex on POPC/POPS nanodiscs
Sample
  • Complex: full-length p85 alpha and p110 alpha heterodimer/KRas complex bound to POPC/POPS-MSP1E3D1 nanodiscs
    • Protein or peptide: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
    • Protein or peptide: Isoform 2B of GTPase KRas
  • Ligand: 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
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
Keywordslipid 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
GTPase KRas / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsTorosyan H / Natalia J / Verba KA
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)U54CA274502 United States
CitationJournal: Biorxiv / Year: 2025
Title: Structures of the PI3K alpha /KRas complex on lipid bilayers reveal the molecular mechanism of PI3K alpha activation
Authors: Torosyan H / Paul MD / Maker A / Meyer BG / Jura N / Verba KA
History
DepositionFeb 25, 2025-
Header (metadata) releaseMay 20, 2026-
Map releaseMay 20, 2026-
UpdateMay 20, 2026-
Current statusMay 20, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49455.png

Downloads & links

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Map

FileDownload / File: emd_49455.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationstructure of the Class 3 PI3K alpha/KRas complex on POPC/POPS nanodiscs
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 448 pix.
= 366.867 Å		0.82 Å/pix.
x 448 pix.
= 366.867 Å		0.82 Å/pix.
x 448 pix.
= 366.867 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8189 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.416
Minimum - Maximum-1.9232343 - 3.6340852
Average (Standard dev.)-0.00032740878 (±0.04596517)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 366.8672 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_49455_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_49455_half_map_1.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map A

Fileemd_49455_half_map_2.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : full-length p85 alpha and p110 alpha heterodimer/KRas complex bou...

EntireName: full-length p85 alpha and p110 alpha heterodimer/KRas complex bound to POPC/POPS-MSP1E3D1 nanodiscs
Components
  • Complex: full-length p85 alpha and p110 alpha heterodimer/KRas complex bound to POPC/POPS-MSP1E3D1 nanodiscs
    • Protein or peptide: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
    • Protein or peptide: Isoform 2B of GTPase KRas
  • Ligand: 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
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER

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Supramolecule #1: full-length p85 alpha and p110 alpha heterodimer/KRas complex bou...

SupramoleculeName: full-length p85 alpha and p110 alpha heterodimer/KRas complex bound to POPC/POPS-MSP1E3D1 nanodiscs
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 232.609 KDa

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Macromolecule #1: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit ...

MacromoleculeName: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: phosphatidylinositol-4,5-bisphosphate 3-kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.822578 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYYHHHHHH DYDIPTTENL YFQGAMGSMP PRPSSGELWG IHLMPPRILV ECLLPNGMIV TLECLREATL ITIKHELFKE ARKYPLHQL LQDESSYIFV SVTQEAEREE FFDETRRLCD LRLFQPFLKV IEPVGNREEK ILNREIGFAI GMPVCEFDMV K DPEVQDFR ...String:
MSYYHHHHHH DYDIPTTENL YFQGAMGSMP PRPSSGELWG IHLMPPRILV ECLLPNGMIV TLECLREATL ITIKHELFKE ARKYPLHQL LQDESSYIFV SVTQEAEREE FFDETRRLCD LRLFQPFLKV IEPVGNREEK ILNREIGFAI GMPVCEFDMV K DPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK IN HDCVPEQ VIAEAIRKKT RSMLLSSEQL KLCVLEYQGK YILKVCGCDE YFLEKYPLSQ YKYIRSCIML GRMPNLMLMA KES LYSQLP MDCFTMPSYS RRISTATPYM NGETSTKSLW VINSALRIKI LCATYVNVNI RDIDKIYVRT GIYHGGEPLC DNVN TQRVP CSNPRWNEWL NYDIYIPDLP RAARLCLSIC SVKGRKGAKE EHCPLAWGNI NLFDYTDTLV SGKMALNLWP VPHGL EDLL NPIGVTGSNP NKETPCLELE FDWFSSVVKF PDMSVIEEHA NWSVSREAGF SYSHAGLSNR LARDNELREN DKEQLK AIS TRDPLSEITE QEKDFLWSHR HYCVTIPEIL PKLLLSVKWN SRDEVAQMYC LVKDWPPIKP EQAMELLDCN YPDPMVR GF AVRCLEKYLT DDKLSQYLIQ LVQVLKYEQY LDNLLVRFLL KKALTNQRIG HFFFWHLKSE MHNKTVSQRF GLLLESYC R ACGMYLKHLN RQVEAMEKLI NLTDILKQEK KDETQKVQMK FLVEQMRRPD FMDALQGFLS PLNPAHQLGN LRLEECRIM SSAKRPLWLN WENPDIMSEL LFQNNEIIFK NGDDLRQDML TLQIIRIMEN IWQNQGLDLR MLPYGCLSIG DCVGLIEVVR NSHTIMQIQ CKGGLKGALQ FNSHTLHQWL KDKNKGEIYD AAIDLFTRSC AGYCVATFIL GIGDRHNSNI MVKDDGQLFH I DFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PE LQSFDDI AYIRKTLALD KTEQEALEYF MKQMNDAHHG GWTTKMDWIF HTIKQHALN

UniProtKB: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

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Macromolecule #2: Isoform 2B of GTPase KRas

MacromoleculeName: Isoform 2B of GTPase KRas / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: small monomeric GTPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.516656 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
GMTEYKLVVV GAGGVGKSAL TIQLIQNHFV DEYDPTIEDS YRKQVVIDGE TCLLDILDTA GQEEYSAMRD QYMRTGEGFL CVFAINNTK SFEDIHHYRE QIKRVKDSED VPMVLVGNKC DLPSRTVDTK QAQDLARSYG IPFIETSAKT RQGVDDAFYT L VREIRKHK EKMSKDGKKK KKKSKTKCVI M

UniProtKB: GTPase KRas

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Macromolecule #3: tert-butyl [2-(2-{[(2P)-2-{4-[4-(2-amino-2-oxoethyl)-2-fluoroanil...

MacromoleculeName: 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
type: ligand / ID: 3 / Number of copies: 1 / Formula: A1AZD
Molecular weightTheoretical: 581.658 Da

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER

MacromoleculeName: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / type: ligand / ID: 5 / Number of copies: 1 / Formula: GNP
Molecular weightTheoretical: 522.196 Da
Chemical component information

ChemComp-GNP:
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GppNHp, GMPPNP, energy-carrying molecule analogue*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5 / Details: 50 mM Tris-HCL, 150 mM NaCl, 1mM TCEP
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GRAPHENE OXIDE / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 5 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 47.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2870914
CTF correctionSoftware - Name: cryoSPARC (ver. 4.3.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.3.1) / Number images used: 117424
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.3.1)
FSC plot (resolution estimation)

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