9NIF

Cryo-EM structure of the PI3K alpha/KRas complex on POPC/POPS/PIP2 nanodiscs low-pass filtered to 5 angstroms

This is a non-PDB format compatible entry.

Summary for 9NIF

• Entry DOI: 10.2210/pdb9nif/pdb
• EMDB information: 49460
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Isoform 2B of GTPase KRas, (2R)-3-{[(R)-HYDROXY{[(1R,2R,3S,4R,5R,6S)-2,3,6-TRIHYDROXY-4,5-BIS(PHOSPHONOOXY)CYCLOHEXYL]OXY}PHOSPHORYL]OXY}PROPANE-1 ,2-DIYL DIBUTANOATE, ... (6 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: 2
• Total formula weight: 151101.75

Authors

Torosyan, H.,Natalia, J.,Verba, K.A. (deposition date: 2025-02-26, release date: 2026-05-20, Last modification date: 2026-07-29)

Primary citation

Torosyan, H.,Paul, M.D.,Meyer, B.G.,Maker, A.,Jura, N.,Verba, K.A.
Structures of the PI3K alpha /KRas complex on lipid bilayers reveal molecular mechanisms of PI3K alpha activation.
Mol.Cell, 86:2858-, 2026

PubMed Abstract: PI3Kα is a potent oncogene that converts PIP2 to PIP3 at the plasma membrane upon activation by receptor tyrosine kinases and Ras. To understand the molecular mechanism of PI3Kα activation, we used cryo-electron microscopy to visualize the conformational states that underlie its transition to an active signaling complex. Here, we present structures of the PI3Kα/KRas complex embedded in lipid nanodiscs, revealing a rich ensemble of PI3Kα conformations that capture the progressive release of key inhibitory domains from the PI3Kα catalytic core. PIP2 triggers significant restructuring of active site regulatory motifs while an 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, dimeric PI3Kα amplifies Akt signaling in response to growth factor stimulation. Collectively, these structures map the conformational landscape of PI3Kα activation and reveal previously unexplored interfaces for potential therapeutic targeting.

PubMed: 42349404
DOI: 10.1016/j.molcel.2026.06.010

Experimental method

ELECTRON MICROSCOPY (5 Å)