Characterizing the role of extracellular domain in GLP-1R biased agonism

Le résumé fourni par la source

The biased agonism of glucagon-like peptide-1 receptor (GLP-1R) plays a key role in the efficacy and side effects of drugs used to treat type II diabetes mellitus and obesity. Despite its therapeutic potential, the mechanisms underlying GLP-1R biased agonism remain poorly understood. In this study, we investigate the role of the extracellular domain (ECD) in GLP-1R signaling bias through saturation mutagenesis at seven key sites. We examined 126 mutations and identified several that selectively abolished β-arrestin recruitment while retaining cAMP production. Additionally, we employed a large language model (LLM) to interpret the functional impacts of these mutations, uncovering correlations between sequence features and signaling outcome. These findings provide new insight into the "two-domain" model of class B1 G protein-coupled receptors (GPCRs), highlighting the ECD's role in biased agonism and offering novel information for designing more effective and selective GLP-1R agonists. • A comprehensive set of 126 mutations at 7 key sites in the GLP-1R ECD have been investigated • Saturation mutagenesis revealed molecular interactions between the GLP-1R ECD and peptide ligand • Mutations in the GLP-1R ECD (E68 and R121) can modulate GLP-1R signaling bias • A novel strategy to interpret relationship between mutations and signaling bias in GLP-1R has been explored

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