Figure 8
From: Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease
Proposed model of TcAkt activation via disruption of its autoinhibitory interface upon PIP-binding. TcAkt PH domain is shown in turquoise, TcAkt kinase domain in sand and the C-tail in lavender. (a) Interdomain contacts between the hydrophobic tip of the PH domain (sticks colored in turquoise) and the kinase domain (sticks colored in sand) are shown as zoomed detail. Phosphorylation site T290 is colored in red. Conserved residues are marked with an asterisk (*). (b) Ligand induced bending of TcAkt loop β1-β2. Superposition of TcAkt apo-form (a) and PIP-bound TcAkt determined by MD simulations (pink). Red arrow indicates conformational changes upon binding to PIPs. (c) TcAkt is present in a closed conformation (inactive) and gets recruited to the membrane. The PH domain and the kinase domain are interacting via an autoinhibitory interface. (d) The binding of the TcAkt PH domain to PIP molecules in the membrane induces conformational changes of the hydrophobic tip (F16, Y17) of the PH domain loop β1-β2, leading to an opening of the structure and the disruption of the intramolecular autoinhibitory interface including a surface exposure of otherwise buried phosphorylation site T290.
