9EBQ

Peptide 2 (GLP-1 (ACPC18)) bound to GLP-1R/Gs complex (conformer 2)

Summary for 9EBQ

• Entry DOI: 10.2210/pdb9ebq/pdb
• EMDB information: 47884
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (5 entities in total)
• Functional Keywords: g protein, agonist, backbone, glp-1, glucagon, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 160106.49

Authors

Cary, B.P.,Hager, M.V.,Mariam, Z.,Morris, R.K.,Belousoff, M.J.,Deganutti, G.,Wootten, D.,Sexton, P.M.,Gellman, S.H. (deposition date: 2024-11-12, release date: 2025-03-26, Last modification date: 2025-04-16)

Primary citation

Cary, B.P.,Hager, M.V.,Mariam, Z.,Morris, R.K.,Belousoff, M.J.,Deganutti, G.,Sexton, P.M.,Wootten, D.,Gellman, S.H.
Prolonged signaling of backbone-modified glucagon-like peptide- 1 analogues with diverse receptor trafficking.
Proc.Natl.Acad.Sci.USA, 122:e2407574122-e2407574122, 2025

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 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.

PubMed: 40168114
DOI: 10.1073/pnas.2407574122

Experimental method

ELECTRON MICROSCOPY (3.16 Å)