PI3Ka and their downstream effectors: the crossroad of cancer, diabetes and inflammation
The project aims to understand the molecular and structural mechanism of activation and inhibition of class I phosphoinositide 3 kinases. These lipid kinases are the key signaling element in a diverse array of cellular functions such as cell growth, motility, and, and a validated targets for pharmacological intervention. Deregulation of PI3K pathway is implicated in a variety of diseases including thromboembolism, inflammation, autoimmune diseases and cancer. We determined the structure of PI3Ka in heterodimeric form showing all five domains of p110a in complex with the nSH2 and iSH2 domains of the p85a. We determined the structure of the somatic p110a H1047R/niSH2 mutant alone and in complex with the inhibitor wortmannin. The PI3K enzyme, as the hub of the PI3K/AKT/ mTOR pathway, presents an opportunity where structural biology, enzymology, and inhibitor design converge to both elucidate mechanisms of action and provide initial hits for targeted therapies.