Structural insights of AKT and its activation mechanism for drug development

Abstract AKT1, a serine/threonine kinase, is pivotal in signaling and regulating cell survival, proliferation, and metabolism. This review focuses on the structural insights and the essential features required for its active conformation. AKT belongs to the AGC kinase group and has three isoforms: AKT1, AKT2, and AKT3. AKT has three functional regions: PH domain, kinase domain, and hydrophobic motif. AKT1 activation involves intricate conformational changes, including transitions in the αC-in, DFG-in, G-loop, activation loop, and PH domain out, S-spine and R-spine formation, as well as phosphorylation at Thr 308 and Ser 473, which enable AKT1 to adopt active conformation. The analysis highlights the limitations of the AlphaFold-predicted AKT1 structure, which lacks key elements of the active state, including ATP, magnesium ion coordination, phosphatidylinositol-(1,3,4,5)-tetraphosphate, substrate peptide, and phosphorylation at Thr 308 and Ser 473. This study underscores the necessity of these features for stabilizing the kinase domain and facilitating efficient substrate phosphorylation. By consolidating structural insights and activation mechanisms, this review aims to inform the development of computational models and targeted therapeutics for AKT1 activators in diseases such as hepatic ischemia–reperfusion injury, cerebral ischemia, acute hepatic failure, subarachnoid hemorrhage, and alzheimer’s disease.