Laboratoire de Biologie Physico-Chimique des Protéines Membranaires, UMR 7099, CNRS, Université de Paris, Institut de Biologie Physico-Chimique (FRC 550), Paris, France
Marjorie Damian
IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France
Laboratoire de Biologie et Pharmacologie Appliquées, UMR 8113 CNRS, Ecole Normale Supérieure Paris-Saclay, Gif-sur-Yvette, France; Programa de Computação Científica, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Pedro Renault
IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France
Antoniel AS Gomes
IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France; Laboratório de Física Biológica, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France
Laurent J Catoire
Laboratoire de Biologie Physico-Chimique des Protéines Membranaires, UMR 7099, CNRS, Université de Paris, Institut de Biologie Physico-Chimique (FRC 550), Paris, France
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.
