| Autor: |
Patrick M. Sexton, Peishen Zhao, Brian P. Cary, Samuel H. Gellman, Tin T. Truong, Sarah J. Piper, Radostin Danev, Matthew J. Belousoff, Denise Wootten |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
Recent advances in G protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multi-dimensional signal propagation mediated by these receptors is, in part, dependent on their conformational mobility. However, the relationship between receptor function and static structures determined via crystallography or cryo-electron microscopy is not always clear. This study examines the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide-1 receptor (GLP-1R), an important clinical target. We employ variants of the peptides GLP-1 and exendin-4 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 exendin-4 analogue, the GLP-1R and Gs protein revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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