Role of a Novel PH-Kinase Domain Interface in PKB/Akt Regulation: Structural Mechanism for Allosteric Inhibition

摘要: Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/threonine protein kinases. It is a key regulator downstream various growth factors and hormones involved in malignant transformation chemo-resistance. Full-length PKB has not been crystallised, thus studying molecular mechanisms that are its regulation relation structure have simple. Recently, dynamics between inactive active conformer at level described. The maintenance PKB's state via interaction PH domains prevents activation loop be phosphorylated by upstream activator, phosphoinositide-dependent kinase-1 (PDK1). By using multidisciplinary approach including modelling, classical biochemical assays, Forster resonance energy transfer (FRET)/two-photon fluorescence lifetime imaging microscopy (FLIM), detailed model depicting different conformation was demonstrated. These findings turn clarified mechanism inhibition AKT inhibitor VIII (a specific allosteric inhibitor) illustrated selectivity towards isoforms. Furthermore, these allude possible function C-terminus sustaining PKB. This study presents essential insights into quaternary conformation. An understanding critical for elucidating mode discovering how modulate activity. drug implications determining other inhibitors opening up opportunities design new generations modulator drugs.