LAUSR

Class I phosphoinositide-3-kinases (PI3Ks) phosphorylate PIP2 at its 3' inositol position to generate PIP3, a second messenger that influences signaling cascades regulating cellular growth, survival, and proliferation. Previous studies have suggested that PI3Kα activation involves dislodging the p85α nSH2 domain from the p110α catalytic subunit by binding activated receptor tyrosine kinases. We carried out molecular dynamics simulations to determine, mechanistically and structurally, how PI3Kα conformations are influenced by physiological effectors and the nSH2 domain. We demonstrate that changes in protein dynamics mediated by allosteric regulation significantly increase the population of catalytically competent states without changing the enzyme ground-state structure. Furthermore, we demonstrate that modulation of active-site residue interactions with enzyme substrates can reciprocally influence nSH2 domain dynamics. Together, these results suggest that dynamic allostery plays a role in populating the catalytically competent conformation of PI3Kα, and provide a key platform for the design of novel chemotherapeutic PI3Kα inhibitors.