National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM056414
米国
National Health and Medical Research Council (NHMRC, Australia)
1154434
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1155302
オーストラリア
Australian Research Council (ARC)
IC200100052
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1150083
オーストラリア
National Health and Medical Research Council (NHMRC, Australia)
1184726
オーストラリア
National Science Foundation (NSF, United States)
DGE-1747503
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
T32 GM008349
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
T32 GM008505
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35 GM151985
米国
引用
ジャーナル: Proc Natl Acad Sci U S A / 年: 2025 タイトル: Prolonged signaling of backbone-modified glucagon-like peptide- analogues with diverse receptor trafficking. 著者: Brian P Cary / Marlies V Hager / Zamara Mariam / Rylie K Morris / Matthew J Belousoff / Giuseppe Deganutti / Patrick M Sexton / Denise Wootten / Samuel H Gellman / 要旨: 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.