Structure-function models of novel mutants in the PI3K-PTEN-AKT pathway. Structure-function models of novel mutants in the PI3K-PTEN-AKT pathway. A, schematic.

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Structure-function models of novel mutants in the PI3K-PTEN-AKT pathway. Structure-function models of novel mutants in the PI3K-PTEN-AKT pathway. A, schematic protein domains of AKT showing locations of E17K (AKT3) and Q79K (AKT1) substitutions in the PHD (underlined portion represented in 3D). Merged structures of apo AKT1Q79K (purple) and IP4-bound AKT1Q79K (blue) with zoomed-in image (PIP3, orange) showing locations of E17 (green) and relative positions of WT Q79 (yellow) and mutant K79 (red). B, schematic protein domains of PIK3CA (p110α) and PIK3R2 (p85β) showing locations of the PIK3CAD350G (C2 domain) and PIK3CAE545G (helical domain) substitutions. Underlined portions of PIK3CA and homologous PIK3R1 represented as a 3D heterodimer [PIK3CA WT, purple; PIK3CAD350G, blue; niSH2 domain of PIK3R1 (p85α), magenta]. A zoomed-in view of the interface between the C2 domain of PIK3CA and niSH2 domain of PIK3R2 suggesting the D350G (D350, yellow; G350, red) substitution likely abolishes a critical interaction with the highly conserved S565 (orange) of PIK3R2. C, schematic protein domains of PIK3CA (p110α) and PIK3R2 (p85β) showing location of the PIK3R2N561D substitution in the iSH helical linker domain. PIK3CA WT (aa 31-515; magenta) in complex with a merged niSH2 domain structure of PIK3R2 WT (purple) and PIK3R2N561D (blue). A zoomed-in view of the interface between the C2 domain of PIK3CA and niSH2 domain of PIK3R2 showing the interaction between PIK3R2N561 (yellow) and PIK3CAN345 (orange) being disrupted by the PIK3R2N561D mutant (red). D, schematic protein domains of PTEN showing the locations of the frameshift mutation in codon 40 and the deletion of M134. Merged structures of the full-length PTEN WT (purple) with M134 highlighted (yellow) and PTENM134del (blue) in the dual-specificity phosphatase domain bound by the inhibitor tartrate (orange). A zoomed-in view showing how deletion of the highly conserved M134 (yellow) may destabilize an alpha helical structure proximal to the P loop and alters the critical side chain conformations of the P loop, which is critical for phosphatase activity. Hubing Shi et al. Cancer Discovery 2014;4:80-93 ©2014 by American Association for Cancer Research