biostudies-literatureChen YSLeona M. and Harry B. Helmsley Charitable TrustHHS | NIH | National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK NIH HHSAmerican Diabetes AssociationDiabetes Research ConnectionJDRFe2103518118https://www.ebi.ac.uk/biostudies/studies/S-EPMC8325334biostudies-literatureUnknown118(30)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 (<i>meta</i>-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 Proceedings of the National Academy of Sciences of the United States of AmericaInsertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone-receptor activation.PMC8325334R01 DK127761R01 DK040949Project number 211-08-RA-1493-PDF-2017-380-A-N7-13-IN-312017PG-T1D007Lawrence MCWeiss MAChatterjee DDhayalan BJarosinski MALiu YPhillips NBYang YChen YSGleaton JMichael MDBroadwater LHattier TfalseInsertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone-receptor activation.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 (<i>meta</i>-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 2021-01-01T00:00:00Z2021 Jul2026-05-08T10:39:19.271Z2022-02-11T16:14:04.015ZS-EPMC83253343429014510.1073/pnas.2103518118