7S3I

Ex4-D-Ala bound to the glucagon-like peptide-1 receptor/g protein complex (conformer 2)

Summary for 7S3I

• Entry DOI: 10.2210/pdb7s3i/pdb
• Related: 7S1M
• EMDB information: 24825
• 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: glucagon, d-ala, exendin, glp-1, glp-1r, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 160122.49

Authors

Belousoff, M.J.,Piper, S.J.,Danev, R. (deposition date: 2021-09-07, release date: 2022-01-05, Last modification date: 2024-10-23)

Primary citation

Cary, B.P.,Deganutti, G.,Zhao, P.,Truong, T.T.,Piper, S.J.,Liu, X.,Belousoff, M.J.,Danev, R.,Sexton, P.M.,Wootten, D.,Gellman, S.H.
Structural and functional diversity among agonist-bound states of the GLP-1 receptor.
Nat.Chem.Biol., 18:256-263, 2022

PubMed Abstract: Recent advances in G-protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multidimensional signal propagation mediated by these receptors depends, in part, on their conformational mobility; however, the relationship between receptor function and static structures is inherently uncertain. Here, we examine the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide 1 receptor (GLP-1R), an important clinical target. We use variants of the peptides GLP-1 and exendin-4 (Ex4) to explore the interplay between helical propensity near the agonist N terminus and the ability to bind to and activate the receptor. Cryo-EM analysis of a complex involving an Ex4 analog, the GLP-1R and G heterotrimer revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data, along with molecular dynamics (MD) simulations, suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy.

PubMed: 34937906
DOI: 10.1038/s41589-021-00945-w

Experimental method

ELECTRON MICROSCOPY (2.51 Å)