Journal article
Insertion of a Synthetic Switch Into Insulin Provides Metabolite-Dependent Regulation of Hormone-Receptor Activation
Yen-Shan Chen, Jeremy Gleaton, Yanwu Yang, Balamurugan Dhayalan, Nelson B Phillips, Yule Liu, Laurie Broadwater, Mark Jarosinski, Deepak Chatterjee, Michael C Lawrence, Thomas Hattier, Dodson M Michael, Michael Aaron Weiss
Journal of the Endocrine Society | The Endocrine Society | Published : 2021
Abstract
Abstract Insulin signaling requires conformational change: whereas the free hormone and its receptor each adopt autoinhibited conformations, their binding leads to large-scale structural reorganization. To test the coupling between insulin’s “opening” and receptor activation, we inserted an artificial ligand-dependent switch into insulin. 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 GlyA1) and internal diol (3,4-dihydroxybenzoate at LysB28). The sensor recognizes monosaccharides (fruct..
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