9EBO

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

9EBO の概要

• エントリーDOI: 10.2210/pdb9ebo/pdb
• EMDBエントリー: 47883
• 分子名称: 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, ... (6 entities in total)
• 機能のキーワード: g protein, agonist, backbone, glp-1, glucagon, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 163433.20

構造登録者

Cary, B.P.,Hager, M.V.,Mariam, Z.,Morris, R.K.,Belousoff, M.J.,Deganutti, G.,Wootten, D.,Sexton, P.M.,Gellman, S.H. (登録日: 2024-11-12, 公開日: 2025-03-26, 最終更新日: 2025-04-16)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.13 Å)