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| Title | Prolonged signaling of backbone-modified glucagon-like peptide- analogues with diverse receptor trafficking. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 122, Issue 14, Page e2407574122, Year 2025 |
| Publish date | Apr 8, 2025 |
 Authors | Brian P Cary / Marlies V Hager / Zamara Mariam / Rylie K Morris / Matthew J Belousoff / Giuseppe Deganutti / Patrick M Sexton / Denise Wootten / Samuel H Gellman /    |
| PubMed Abstract | Signal duration and subcellular location are emerging as important facets of G protein-coupled receptor (GPCR) function. The glucagon-like peptide-1 receptor (GLP-1R), a clinically relevant class B1 ...Signal duration and subcellular location are emerging as important facets of G protein-coupled receptor (GPCR) function. The glucagon-like peptide-1 receptor (GLP-1R), a clinically relevant class B1 GPCR, stimulates production of the second messenger cyclic adenosine monophosphate (cAMP) upon activation by the native hormone, GLP-1. cAMP production continues after the hormone-receptor complex has been internalized via endocytosis. Here, we report GLP-1 analogues that induce prolonged signaling relative to GLP-1. A single β-amino acid substitution at position 18, with the residue derived from (,)--2-aminocyclopentanecarboxylic acid (ACPC), enhances signaling duration with retention of receptor endocytosis. Pairing ACPC at position 18 with a second substitution, α-aminoisobutyric acid (Aib) at position 16, abrogates endocytosis, but prolonged signaling is maintained. Prolonged signaling is sensitive to the structure of the β residue at position 18. Cryoelectron microscopy structures of two GLP-1 analogues bound to the GLP-1R:Gs complex suggest substantial alterations to bound peptide structure and dynamics compared to the GLP-1:GLP-1R:Gs complex. These structural findings strengthen an emerging view that agonist dynamics in the receptor-bound state influence signaling profiles. Our results advance understanding of the structural underpinnings of receptor activation and introduce tools for exploring the impact of spatiotemporal signaling profiles following GLP-1R activation. |
 External links | Proc Natl Acad Sci U S A / PubMed:40168114 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.13 - 3.44 Å |
| Structure data | EMDB-47882, PDB-9ebn: EMDB-47883, PDB-9ebo: EMDB-47884, PDB-9ebq: |
| Source |
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 Keywords | MEMBRANE PROTEIN / G protein / agonist / backbone / GLP-1 / glucagon |
homo sapiens (human)
lama glama (llama)