Abstract 3060 Structures of the PI3Ka/KRas complex on lipid bilayers reveal the molecular mechanism of PI3Ka activation

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.