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Activation of a G-protein-coupled receptor by its natural ligand, ghrelin

Elucidating the molecular mechanisms involved in the recognition of natural peptides by their G protein-coupled receptors is a major challenge in pharmacology. Two teams from the Occitania region, one from Toulouse (A. Milon, "Integrative Biological NMR" team, IPBS) and the other from Montpellier (J.-L. Banères, "Cellular Pharmacology" team, IBMM), have joined forces to implement advanced biochemical and biophysical approaches and solve the structure of a peptide hormone, ghrelin, in its receptor-related state.


Ghrelin is a major player in human physiology, involved in actions as diverse as growth hormone secretion, appetite, glucose homeostasis, but also drug and alcohol addiction, depression or certain cancers. These data, published on August 27 in Proc Natl Acad Sci USA, show that, far from a static key-lock vision, the dynamics of the peptide in its linked state plays a major role in its interactions with its receptor. These new concepts and data will contribute to a better understanding of the functioning of the ghrelin-receptor pair and to the development of new ligands of this receptor for use in therapy or diagnosis. They are part of the long history of ghrelin research conducted at IBMM over the past 15 years, which led to the launch in 2019 of a non-peptide agonist of its receptor for the diagnosis of growth hormone deficiency in adults. They also illustrate the crucial contribution of NMR, combined here with molecular pharmacology and modelling approaches, in understanding the functional dynamics of living organisms.


Sans titre.png(A) Set of conformations illustrating the structure and dynamics of ghrelin within its receptor. This set of structures was determined by NMR and molecular modeling, with a peptide labelled with stable isotopes and recombinant receptor. The octanoyl chain plays a central role in the hydrophobic organization of neighbouring amino acids in the N-terminal half of the peptide, which is strictly necessary for the activation of the receptor. The high dynamics of the C-terminal half is illustrated by the diversity of the structures observed. (B) Model of the ghrelin-receptor complex derived from molecular dynamics simulations and reporting experimental data.



Structure and dynamics of G protein-coupled receptor–bound ghrelin reveal the critical role of the octanoyl chain. Guillaume Ferré, Maxime Louet, Oliver Saurel, Bartholomé Delort, Georges Czaplicki, Céline M’Kadmi, Marjorie Damian, Pedro Renault, Sonia Cantel, Laurent Gavara, Pascal Demange, Jacky Marie, Jean-Alain Fehrentz, Nicolas Floquet, Alain Milon*, and Jean-Louis Banères*. Proc Natl Acad Sci USA, 27 August 2019. DOI : 10.1073/pnas.1905105116


CNRS Researcher l Alain Milon l T +33 5 61 17 54 23 l