Structure and dynamics of G protein-coupled receptor-bound ghrelin reveal the critical role of the octanoyl chain.
GPCR
NMR
acylation
coarse-grain modeling
ghrelin
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
27 08 2019
27 08 2019
Historique:
pubmed:
17
8
2019
medline:
31
3
2020
entrez:
17
8
2019
Statut:
ppublish
Résumé
Ghrelin plays a central role in controlling major biological processes. As for other G protein-coupled receptor (GPCR) peptide agonists, the structure and dynamics of ghrelin bound to its receptor remain obscure. Using a combination of solution-state NMR and molecular modeling, we demonstrate that binding to the growth hormone secretagogue receptor is accompanied by a conformational change in ghrelin that structures its central region, involving the formation of a well-defined hydrophobic core. By comparing its acylated and nonacylated forms, we conclude that the ghrelin octanoyl chain is essential to form the hydrophobic core and promote access of ghrelin to the receptor ligand-binding pocket. The combination of coarse-grained molecular dynamics studies and NMR should prove useful in improving our mechanistic understanding of the complex conformational space explored by a natural peptide agonist when binding to its GPCR. Such information should also facilitate the design of new ghrelin receptor-selective drugs.
Identifiants
pubmed: 31416915
pii: 1905105116
doi: 10.1073/pnas.1905105116
pmc: PMC6717258
doi:
Substances chimiques
Ghrelin
0
Receptors, G-Protein-Coupled
0
Banques de données
PDB
['6H3E']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
17525-17530Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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