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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Dokumenter

  • Wen Sun
  • Li-Nan Chen
  • Qingtong Zhou
  • Li-Hua Zhao
  • Dehua Yang
  • Huibing Zhang
  • Zhaotong Cong
  • Dan-Dan Shen
  • Fenghui Zhao
  • Fulai Zhou
  • Xiaoqing Cai
  • Yan Chen
  • Yan Zhou
  • Wijnand J. C. van der Velden
  • Suwen Zhao
  • Yi Jiang
  • H. Eric Xu
  • Yan Zhang
  • Ming-Wei 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 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.

OriginalsprogEngelsk
TidsskriftCell Research
Vol/bind30
Udgave nummer12
Sider (fra-til)1098-1108
ISSN1001-0602
DOI
StatusUdgivet - 2020

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