Abstract 2301: Atomic-level insights into PI3K activation

Abstract

Abstract PI3Kα (PIK3CA) is the second highly mutated oncogene in cancer. It is activated by the receptor tyrosine kinases (RTKs) and Ras on the membrane, regulating the PI3K/Akt/mTOR pathway for the cell growth and proliferation. PI3Kα is an obligate dimer with p110α catalytic subunit and p85α regulatory subunit. Their interactions stabilize and maintain PI3Kα in the inactive state. At the molecular level, the activation of PI3Kα requires two events, (i) the release of nSH2 by phosphorylated tyrosine (pY) motif in the RTK and (ii) the membrane localization facilitated by Ras. The mechanism of PI3Kα activation at the atomic level suggests that PI3Kα undergoes the significant conformational change upon nSH2 release. The iSH2 in p85α subunit moves, which facilitates the membrane interactions and catalysis. The activation loop (a-loop) in the kinase domain becomes more flexible, exposing the basic residues for the substrate binding. The activation mechanism expedites our understanding of the PI3K autoinhibition, activation, and catalysis. By collecting and analyzing the available PI3K structures, we have identified the structural features that distinguish the inactive and active class IA PI3Ks. The a-loop is “collapsed” with kα11 in the regulatory arch “IN” in the inactive PI3Ks. Upon activation, the a-loop becomes “extended” and kα11 moves “OUT”. These features provide the functional explanations for both hotspot and weak oncogenic mutations and indicate their additive effects. The mechanism reveals a principle for PI3K allosteric drug discovery. The inhibitors that may modulate the iSH2 dynamics can allosterically prevent PI3K activation in the signaling pathways. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Citation Format: Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. Atomic-level insights into PI3K activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2301.