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In addition to 564 semaglutide analogues (supplementary file sema.txt ) with site-specific missense mutations, this study delves into the sequence space of GLP-1R ECD and semaglutide, and uncovers an electrostatic scaffold of intermolecular salt bridges at the ligand-receptor binding interface, which help stabilize the complex structure to enhance GLP-1R activation, providing a robust framework for the development of next-generation GLP-1R agonists with improved efficacy [4346]