Structure and dynamics of semaglutide- and taspoglutide-bound GLP-1R-Gs complexes

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The glucagon-like peptide-1 receptor (GLP-1R) regulates insulin secretion, carbohydrate metabolism, and appetite and is an important target for treatment of type 2 diabetes and obesity. Multiple GLP-1R agonists have entered into clinical trials, with some, such as semaglutide, progressing to approval. Others, including taspoglutide, failed due to the high incidence of side effects or insufficient efficacy. GLP-1R agonists have a broad spectrum of signaling profiles, but molecular understanding is limited by a lack of structural information on how different agonists engage with the GLP-1R. Here, we report cryoelectron microscopy (cryo-EM) structures and cryo-EM 3D variability analysis of semaglutide- and taspoglutide-bound GLP-1R-Gs protein complexes. These reveal similar peptide interactions to GLP-1 but different motions within the receptor and bound peptides, providing insights into the molecular determinants of GLP-1R peptide engagement. 

Original languageEnglish
Article number109374
Number of pages15
JournalCell Reports
Issue number2
Publication statusPublished - 13 Jul 2021


  • cryoelectron microscopy
  • GLP-1R
  • glucagon-like peptide-1 receptor
  • GPCR dynamics
  • GPCRs
  • semaglutide
  • tasopglutide

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