Fig. 2. Structural mechanism of PI3Kα activation by 1938.

a, Structural changes induced by 1938 as assessed by HDX-MS in full-length p110α/p85α, highlighted on the structure of p110α (gray)/niSH2-p85α (green) (pdb:4ZOP). Selection threshhold for significant peptides: a-b difference ≥2.5%, Da difference ≥0.25, p-value <0.05 (unpaired t-test). b, Sigma-weighted density map in blue (2mFo-DFc) for the 1938 ligand (magenta) in the p110α crystal structure. Yellow dashes show predicted H-bonds. c, Crystal structure of 1938 bound to p110α; 1938 (magenta), activation loop (yellow), loop 1002-1016 (kinase/activator interface, slate), predicted H-bonds (yellow dashes). d, Comparison of the 1938-bound p110α with apo-p110α. The 1938-bound structure is shown in cartoon representation, while the apo-model is shown as a superimposed red Cα trace. 1938 shown as magenta blob, PRD-like helix shown in purple. Yellow spheres mark the sites of cancer-associated mutations from the COSMIC database that are near the 1938-binding site (only mutations with >10 reports are shown). Regions showing decreased HDX-MS protection for the common helical domain mutations are colored orange. PIP₂ substrate (slate) has been modelled in the active based on 4OVV. A region of the activation loop (thick worm representation, slate) has been taken from 7PG5 since it is disordered in the 1938-bound structure. Slate spheres represent residues important for PIP₂ recognition (K942 and R949). Chocolate spheres represent residues essential for phosphate transfer (K776, H917 and H936). A bound ATP (blue) has been modelled based on PDB ID 1E8X. The ATP binding loop is coloured yellow. Phosphates in PIP₂ and ATP are shown in red. e, Comparison of 1938-binding pocket in p110α with homologous regions in p110β and p110δ.