ADVANCE ONLINE PUBLICATION |
A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor
Wen Sun1,2,3 , Li-Nan Chen4 , Qingtong Zhou5,6 , Li-Hua Zhao1 , Dehua Yang1,2 , Huibing Zhang4 , Zhaotong Cong7 , Dan-Dan Shen4 , Fenghui Zhao7 , Fulai Zhou1,2 , Xiaoqing Cai1,2 , Yan Chen7 , Yan Zhou1,2 , Sarina Gadgaard8 , Wijnand J. C. van der Velden8 , Suwen Zhao5,9 , Yi Jiang1 , Mette M. Rosenkilde8 , H. Eric Xu1,3,* , Yan Zhang4,10,11,12,* , Ming-Wei Wang1,2,3,6,7,9,*1The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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 Gs 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.