A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor

• Published in: Cell research 2020-12, Vol.30 (12), p.1098-1108
• Main Authors: Sun, Wen, Chen, Li-Nan, Zhou, Qingtong, Zhao, Li-Hua, Yang, Dehua, Zhang, Huibing, Cong, Zhaotong, Shen, Dan-Dan, Zhao, Fenghui, Zhou, Fulai, Cai, Xiaoqing, Chen, Yan, Zhou, Yan, Gadgaard, Sarina, van der Velden, Wijnand J. C., Zhao, Suwen, Jiang, Yi, Rosenkilde, Mette M., Xu, H. Eric, Zhang, Yan, Wang, Ming-Wei
• Format: Article
• Language: English
• Subjects: 101/1; 101/28; 13/109; 631/535/1258/1259; 631/80/86/2363; 82/16; 82/29; 82/80; 82/83; 96/33; 96/95; Biomedical and Life Sciences; C-Terminus; Cell Biology; Crohn's disease; Drug development; Electron microscopy; Feature recognition; G protein-coupled receptors; Glucagon; Glucagon-like peptide 2; Helices; Histidine; Hormones; Intestine; Life Sciences; Metabolic disorders; Peptides; Receptor mechanisms; Receptors; Signal transduction; Therapeutic targets
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/s41422-020-00442-0

Glucagon-like peptides (GLP-1 and GLP-2) are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors (GLP-1R and GLP-2R) which are important drug targets for metabolic disorders and Crohn’s disease, respectively. Despite great progress in GLP-1R structure determination, our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive. Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a G s heterotrimer. To accommodate GLP-2 rather than GLP-1, GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices (TMs) 1, 5, 7 and extracellular loop 1 (ECL1). In contrast to GLP-1, the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique orientation. The middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2, and the GLP-2 C-terminus closely attaches to ECL1, which is the most protruded among 9 class B G protein-coupled receptors (GPCRs). Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation, especially the middle region. These results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics.