7s3i

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

Structural highlights

7s3i is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.51Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GBG2_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity).

Publication Abstract from PubMed

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(s) 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.

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 Nat Chem Biol. 2022 Mar;18(3):256-263. doi: 10.1038/s41589-021-00945-w. Epub 2021 , Dec 22. PMID:34937906[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. Cary BP, Deganutti G, Zhao P, Truong TT, Piper SJ, Liu X, Belousoff MJ, Danev R, Sexton PM, Wootten D, Gellman SH. Structural and functional diversity among agonist-bound states of the GLP-1 receptor. Nat Chem Biol. 2022 Mar;18(3):256-263. PMID:34937906 doi:10.1038/s41589-021-00945-w

Contents


PDB ID 7s3i

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