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A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor.
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.
Afiliación
  • Sun W; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Chen LN; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhou Q; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Zhao LH; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
  • Yang D; iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
  • Zhang H; School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • Cong Z; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Shen DD; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhao F; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhou F; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
  • Cai X; School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • Chen Y; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
  • Zhou Y; School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • Gadgaard S; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • van der Velden WJC; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhao S; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Jiang Y; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Rosenkilde MM; School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • Xu HE; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhang Y; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Wang MW; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, N, DK-2200, Denmark.
Cell Res ; 30(12): 1098-1108, 2020 12.
Article en En | MEDLINE | ID: mdl-33239759
ABSTRACT
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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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptor del Péptido 2 Similar al Glucagón Límite: Humans Idioma: En Revista: Cell Res Año: 2020 Tipo del documento: Article País de afiliación: China
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptor del Péptido 2 Similar al Glucagón Límite: Humans Idioma: En Revista: Cell Res Año: 2020 Tipo del documento: Article País de afiliación: China