9NI4
Cryo-EM structure of the PI3K alpha/KRas/HER3 phosphopeptide complex dimer on POPC/POPS/PIP2 nanodiscs
This is a non-PDB format compatible entry.
Summary for 9NI4
| Entry DOI | 10.2210/pdb9ni4/pdb |
| EMDB information | 49452 |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Isoform 2B of GTPase KRas, 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, ... (5 entities in total) |
| Functional Keywords | lipid kinase, gtpase, oncoprotein, transferase-hydrolase complex, transferase/hydrolase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 300934.79 |
| Authors | |
| Primary citation | Torosyan, H.,Paul, M.D.,Maker, A.,Meyer, B.G.,Jura, N.,Verba, K.A. Structures of the PI3K alpha /KRas complex on lipid bilayers reveal the molecular mechanism of PI3K alpha activation. Biorxiv, 2025 Cited by PubMed 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 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. PubMed: 40196507DOI: 10.1101/2025.03.22.644753 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.61 Å) |
Structure validation
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