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TitleStructure and dynamics of semaglutide- and taspoglutide-bound GLP-1R-Gs complexes.
Journal, issue, pagesCell Rep, Vol. 36, Issue 2, Page 109374, Year 2021
Publish dateJul 13, 2021
AuthorsXin Zhang / Matthew J Belousoff / Yi-Lynn Liang / Radostin Danev / Patrick M Sexton / Denise Wootten /
PubMed AbstractThe 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- ...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.
External linksCell Rep / PubMed:34260945
MethodsEM (single particle)
Resolution2.5 Å
Structure data

22882

7ki0

EMDB-22882, PDB-7ki0:
Semaglutide-bound Glucagon-Like Peptide-1 (GLP-1) Receptor in Complex with Gs protein
Method: EM (single particle) / Resolution: 2.5 Å

22883

7ki1

EMDB-22883, PDB-7ki1:
Taspoglutide-bound Glucagon-Like Peptide-1 (GLP-1) Receptor in Complex with Gs Protein
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-WF1:
17-amino-10-oxo-3,6,12,15-tetraoxa-9-azaheptadecan-1-oic acid

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • lama glama (llama)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / Glucagon-Like peptide-1 (GLP-1) Receptor semaglutide cryoEM / Glucagon-Like peptide-1 (GLP-1) Receptor / taspoglutide

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