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

Wen Sun^1,2,3 , Li-Nan Chen⁴ , Qingtong Zhou^5,6 , Li-Hua Zhao¹ , Dehua Yang^1,2 , Huibing Zhang⁴ , Zhaotong Cong⁷ , Dan-Dan Shen⁴ , Fenghui Zhao⁷ , Fulai Zhou^1,2 , Xiaoqing Cai^1,2 , Yan Chen⁷ , Yan Zhou^1,2 , Sarina Gadgaard⁸ , Wijnand J. C. van der Velden⁸ , Suwen Zhao^5,9 , Yi Jiang¹ , Mette M. Rosenkilde⁸ , H. Eric Xu^1,3,* , Yan Zhang^4,10,11,12,* , Ming-Wei Wang^{1,2,3,6,7,9,*}

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(eric.xu@simm.ac.cn)Yan Zhang(zhang_yan@zju.edu.cn)Ming-Wei Wang(mwwang@simm.ac.cn)

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.

https://doi.org/10.1038/s41422-020-00442-0

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