Concerted conformational dynamics and water movements in the ghrelin G protein-coupled receptor

• Published in: eLife Vol. 10
• Main Authors: Louet, Maxime, Casiraghi, Marina, Damian, Marjorie, Costa, Mauricio Gs, Renault, Pedro, Gomes, Antoniel As, Batista, Paulo R, M'Kadmi, Céline, Mary, Sophie, Cantel, Sonia, Denoyelle, Severine, Ben Haj Salah, Khoubaib, Perahia, David, Bisch, Paulo M, Fehrentz, Jean-Alain, Catoire, Laurent J, Floquet, Nicolas, Banères, Jean-Louis
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 03-09-2021; eLife Sciences Publication; eLife Sciences Publications, Ltd
• Subjects: Biochemistry and Chemical Biology; Biochemistry, Molecular Biology; Biophysics; Chromatography; G protein-coupled receptors; Ghrelin; GPCR; Growth hormones; Humans; Hydration; Labeling; Life Sciences; Ligands; Proteins; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Signal Transduction; signaling; Simulation; Spectrum analysis; Transmembrane domains; signaling; chemical biology; hydration; biochemistry; GPCR; human; E. coli; Chemical biology; Human; Signaling; Hydration; Biochemistry
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.63201

There is increasing support for water molecules playing a role in signal propagation through G protein-coupled receptors (GPCRs). However, exploration of the hydration features of GPCRs is still in its infancy. Here, we combined site-specific labeling with unnatural amino acids to molecular dynamics to delineate how local hydration of the ghrelin receptor growth hormone secretagogue receptor (GHSR) is rearranged upon activation. We found that GHSR is characterized by a specific hydration pattern that is selectively remodeled by pharmacologically distinct ligands and by the lipid environment. This process is directly related to the concerted movements of the transmembrane domains of the receptor. These results demonstrate that the conformational dynamics of GHSR are tightly coupled to the movements of internal water molecules, further enhancing our understanding of the molecular bases of GPCR-mediated signaling.