9NI4
Cryo-EM structure of the PI3K alpha/KRas/HER3 phosphopeptide complex dimer on POPC/POPS/PIP2 nanodiscs
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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 | Torosyan, H.,Natalia, J.,Verba, K.A. (deposition date: 2025-02-25, release date: 2026-05-13, 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 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. 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: 42349404DOI: 10.1016/j.molcel.2026.06.010 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.61 Å) |
Structure validation
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