EMD-24825

Single-particle
2.51 Å
EMD-24825 Deposition: 07/09/2021
Map released: 05/01/2022
Last modified: 23/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-24825

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

EMD-24825

Single-particle
2.51 Å
EMD-24825 Deposition: 07/09/2021
Map released: 05/01/2022
Last modified: 23/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: GLP-1R bound to Ex4-D-Ala, G alpha s, G beta-1, G gamma-2, and Nb35
Fitted models: 7s3i (Avg. Q-score: 0.58)

Deposition Authors: Belousoff MJ , Piper SJ
Structural and functional diversity among agonist-bound states of the GLP-1 receptor.
Cary BP , Deganutti G , Zhao P, Truong TT, Piper SJ , Liu X , Belousoff MJ , Danev R , Sexton PM , Wootten D , Gellman SH
(2022) Nat Chem Biol , 18 , 256 - 263
PUBMED: 34937906
DOI: doi:10.1038/s41589-021-00945-w
ISSN: 1552-4469
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 Gs 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.