PH Domain-Mediated Autoinhibition and Oncogenic Activation of Akt

Previously, we reported that the conformation of autoinhibited Akt, a Ser/Thr protein kinase that plays a central role in metabolism and cancer, may be shifted by small molecule allosteric inhibitors limiting the mechanistic insights from existing X-ray structures that have relied on such compounds (Chu, Viennet, et al, 2020). Here we discover unexpectedly that a single mutation, R86A, in Akt’s PH domain exhibits intensified autoinhibitory features with enhanced PH domain-kinase domain affinity. Structural and biochemical analysis uncovers the importance of a key interaction network involving Arg86, Glu17, and Tyr18 that controls Akt conformation and activity. Our studies also shed light on the molecular basis for E17K Akt activation as an oncogenic driver.