Fig. 1.

The PIP₃ binding site is sequestered in autoinhibited Akt. (A) Structure of autoinhibited Akt1 1 to 445 in complex with a nanobody. Cartoon schematic illustrates domain architecture of Akt1. Color scheme: PH domain, orange; N-lobe of kinase domain, yellow; C-lobe of kinase domain, magenta; C-tail of kinase domain, cyan. Dashed boxes indicate regions of disorder in the structure. (B) Superposition of Akt1 PH domain in complex with Ins(1,3,4,5)P₄ (PDB 1UNQ) with autoinhibited Akt1. Ins(1,3,4,5)P₄ shown in sticks. PIP₃-coordinating residues of PH domain shown in blue sticks (3′ phosphate, K14 and R25; 4’ phosphate, R86). (C) Interaction map of PH-kinase domain interface. Figure produced using Arpeggio (63). Dashed red lines, hydrogen bonds; red springs, cation-pi; blue springs, donor-pi; gray springs carbon-pi; dotted gray lines, hydrophobic van der Waals. (D) Map of disease-associated mutations (red, bold) and mutations that drive growth factor-independent cell survival in vitro (black). Mutations in PH domain shown in orange sticks; mutations in kinase domain shown in magenta sticks. (E) Superposition of structure of Akt1 in complex with inhibitor VIII (3O96) on autoinhibited Akt1. Inward rotation of PH domain indicated by 23° rotation of α1. Rmsd of PH domain over all atoms is 9 Å. (F) Superposition of active Akt1 kinase domain (4EKK) on autoinhibited Akt1. APE-αF loop of autoinhibited Akt1 shown as magenta mesh. Activation loop and APE-αF loop of active Akt1 shown in blue. Zoom: conformation of phosphorylated T308 in activation loop (red sticks) and network of stabilizing interactions.