Structural and molecular conservation of glucagon-like Peptide-1 and its receptor confers selective ligand-receptor interaction

• Published in: Frontiers in endocrinology (Lausanne) Vol. 3; p. 141
• Main Authors: Moon, Mi Jin, Park, Sumi, Kim, Dong-Kyu, Cho, Eun Bee, Hwang, Jong-Ik, Vaudry, Hubert, Seong, Jae Young
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2012
• Subjects: Endocrinology; evolution; G protein-coupled receptors; GLP-1; GLP1R; ligand-receptor interaction; Ortholog; GLP1R; paralog; G protein-coupled receptors; GLP-1; ortholog; evolution; ligand-receptor interaction
• ISSN: 1664-2392; 1664-2392
• DOI: 10.3389/fendo.2012.00141

Glucagon-like peptide-1 (GLP-1) is a major player in the regulation of glucose homeostasis. It acts on pancreatic beta cells to stimulate insulin secretion and on the brain to inhibit appetite. Thus, it may be a promising therapeutic agent for the treatment of type 2 diabetes mellitus and obesity. Despite the physiological and clinical importance of GLP-1, molecular interaction with the GLP-1 receptor (GLP1R) is not well understood. Particularly, the specific amino acid residues within the transmembrane helices and extracellular loops of the receptor that may confer ligand-induced receptor activation have been poorly investigated. Amino acid sequence comparisons of GLP-1 and GLP1R with their orthologs and paralogs in vertebrates, combined with biochemical approaches, are useful to determine which amino acid residues in the peptide and the receptor confer selective ligand-receptor interaction. This article reviews how the molecular evolution of GLP-1 and GLP1R contributes to the selective interaction between this ligand-receptor pair, providing critical clues for the development of potent agonists for the treatment of diabetes mellitus and obesity.