EMD-24825
Ex4-D-Ala bound to the glucagon-like peptide-1 receptor/g protein complex (conformer 2)
EMD-24825
Single-particle2.51 Å
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Map released: 05/01/2022
Last modified: 23/10/2024
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
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
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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
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(2022) Nat Chem Biol , 18 , 256 - 263
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.
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.