Allosteric activation or inhibition of PI3Kγ mediated through conformational changes in the p110γ helical domain

ABSTRACT: To provide additional insight into the molecular mechanisms underlying p110 phosphorylation we carried out hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments on p110 and phosphorylated p110 (90.8% phosphorylated S594/595, 92% phosphorylated S582. When we compared phosphorylated p110 (>90.8% as measured by mass spectrometry at both sites) to unphosphorylated p110 we observed extensive increases in dynamics in the C2, helical domain and kinase domain (Fig. 4A-D). The largest increases in exchange upon phosphorylation were located in the N-terminal region of the helical domain, with the peptides directly adjacent to the phosphorylation site showing almost complete deuterium incorporation at the earliest time points of exchange. This is indicative of significant disruption of the alpha helical secondary structure in this region.

INSTRUMENT(S): impact HD

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: John Burke  

LAB HEAD: John Burke

PROVIDER: PXD040765 | Pride | 2023-07-06

REPOSITORIES: Pride