期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 35, 页码 17525-17530出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1905105116
关键词
GPCR; ghrelin; acylation; NMR; coarse-grain modeling
资金
- Centre Informatique National de l'Enseignement Superieur [A0020707530]
- Partnership for Advanced Computing in Europe [2017174234]
- University of Montpellier
- CNRS, Universite Montpellier, Agence Nationale de la Recherche [ANR-17-CE11-0011]
- CNRS
- Universite Paul Sabatier
- Infrastructures en Biologie Sante et Agronomie European Structural Funds
- Midi-Pyrenees Region
- Chemistry of Molecular and Interfacial Systems (CheMISyst) Labex
- Universite de Montpellier
- High Performance Computing Platform MESO@LR - Occitanie/Pyrenees-Mediterranee Region
- Montpellier Mediterranean Metropole
- Agence Nationale de la Recherche (ANR) [ANR-17-CE11-0011] Funding Source: Agence Nationale de la Recherche (ANR)
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.
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