The glucagon-likepeptide (GLP)-1receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans,enteroendocrine L cells in the distal intestine, a cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two domain-binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable non peptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.
de Graaf, C., Donnelly, D., Wootten, D.
, Lau, J., Sexton, P. M.
, Miller, L. J., Ahn, J-M., Liao, J., Fletcher, M. M.
, Yang, D., Brown, A. J. H., Zhou, C., Deng, J., & Wang, M-W. (2016). Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic successes
. Pharmacological Reviews
(4), 954-1013. https://doi.org/10.1124/pr.115.011395