Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone-receptor activation.

ABSTRACT: Insulin-signaling requires conformational change: whereas the free hormone and its receptor each adopt autoinhibited conformations, their binding leads to structural reorganization. To test the functional coupling between insulin's "hinge opening" and receptor activation, we inserted an artificial ligand-dependent switch into the insulin molecule. Ligand-binding disrupts an internal tether designed to stabilize the hormone's native closed and inactive conformation, thereby enabling productive receptor engagement. This scheme exploited a diol sensor (meta-fluoro-phenylboronic acid at Gly^A1) and internal diol (3,4-dihydroxybenzoate at Lys^B28). The sensor recognizes monosaccharides (fructose > glucose). Studies of insulin-signaling in human hepatoma-derived cells

SUBMITTER: Chen YS 

PROVIDER: S-EPMC8325334 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature