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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
2The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3University of Chinese Academy of Sciences, Beijing 100049, China
4Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
5iHuman Institute, ShanghaiTech University, Shanghai 201210, China
6School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
7School of Pharmacy, Fudan University, Shanghai 201203, China
8Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, DK-2200, Denmark
9School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
10MOE Frontier Science Center for Brain Research and Brain–Machine Integration, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
11Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, Zhejiang 310058, China
12Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang 311121, China
These authors contributed equally: Wen Sun, Li-Nan Chen, Qingtong Zhou, Li-Hua Zhao, Dehua Yang
* Correspondence: H. Eric Xu( Zhang( Wang(

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.


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