Fig. 1. Structure of p110α/p85α and location of PIK3CA oncogenic mutations.

A Domain schematic of both p110α/p85α, with the catalytic core, activation loop (orange), regulatory motif (green) and C-terminus (magenta) of p110α annotated. Same colour scheme has been used to map these features on the structures below. B Oncogenic mutations in p110α mapped on the structure of WT p110α/p85α (PDB: 4OVU³⁹). The frequency of oncogenic mutations from the COSMIC database⁴⁴ as described in panel C is coloured according to the legend with any mutation with a frequency >50 indicated as a sphere. Other features are coloured according to the domain schematic in panel A. The p85 subunit is shown as a transparent blue surface. Cartoons of the two views of PI3K highlighting these features are shown to the right of each structural model. These same cartoon views are used to map all further HDX-MS data. C Frequency of mutations across the primary sequence of PIK3CA from the Catalog of Somatic Mutations in Cancer (COSMIC) database (data from January 2022)⁴⁴. D C-terminus in H1047R adopts a unique confirmation compared to WT (PDB: 3HHM)¹⁷. Features are coloured the same as in panel B. E Above: the sequence of the C-terminus is shown, with mutants coloured blue, and the membrane binding WIF motif in bold⁵⁷. The sequence of a frameshift mutant (N1068KLKR)³⁰ is also shown. Below: Orientation of the C-terminus in the WT (PDB: 4OVU) and H1047R (PDB: 3HHM) crystal structures. The relative positioning of additional oncogenic mutants (M1043I/L, N1044K, G1049R/S) are indicated. The reorientation of the C-terminus (coloured in magenta) that occurs upon H1047R mutation is indicated by the red arrow.