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. 2021 Jul 13;36(2):109374.
doi: 10.1016/j.celrep.2021.109374.

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

Xin Zhang  1 , Matthew J Belousoff  1 , Yi-Lynn Liang  2 , Radostin Danev  3 , Patrick M Sexton  4 , Denise Wootten  5
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Free article

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

Xin Zhang et al. Cell Rep. .
Free article

Abstract

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.

Keywords: GLP-1R; GPCR dynamics; GPCRs; cryoelectron microscopy; glucagon-like peptide-1 receptor; semaglutide; tasopglutide.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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