Structural and functional studies of the glucagon-like peptide-1 (GLP-1) receptor

Abstract

GLP-1 is now being considered as a new treatment for Type 2 diabetes. The requirements, however, for ligand binding and activation to the GLP-1 receptor are currently unknown. A c-myc/his epitope tagged N-terminal GLP-1 receptor domain (Nt GLP-1 Rc) and a V5/his epitope tagged GLP-1 receptor was expressed in Sf9 cells. Cross-linking studies revealed a direct physical interaction between \sp125I-GLP-1 (7-36)NH\sb2 and Nt GLP-1 Rc implicating this region in ligand binding. To gain an understanding of ligand-receptor interaction, modified GLP-1 peptides were assessed for their ability to interact. Glutamate at position 3 and glycine at position 4 were crucial for receptor activation. The C-terminal region was essential for receptor binding. In conclusion, our studies suggest that Nt GLP-1 Rc interacts with the C-terminal region of GLP-1. The structure-function studies of the GLP-1 receptor and its ligand could aid in the design of potential GLP-1 analogues for future NIDDM therapy.