Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants - LIGAN platform - LILLE Accéder directement au contenu
Article Dans Une Revue ACS Pharmacology & Translational Science Année : 2021

Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants

Xavier Deupi
Wenwen Gao
  • Fonction : Auteur
Ralf Jockers

Résumé

Melatonin is a hormone mainly produced by the pineal gland and MT1 is one of the two G protein-coupled receptors (GPCRs) mediating its action. Despite an increasing number of available GPCR crystal structures, the molecular mechanism of activation of a large number of receptors, including MT1, remains poorly understood. The purpose of this study is to elucidate the structural elements involved in the process of MT1’s activation using naturally occurring variants affecting its function. Thirty-six nonsynonymous variants, including 34 rare ones, were identified in MTNR1A (encoding MT1) from a cohort of 8687 individuals and their signaling profiles were characterized using Bioluminescence Resonance Energy Transfer-based sensors probing 11 different signaling pathways. Computational analysis of the experimental data allowed us to group the variants in clusters according to their signaling profiles and to analyze the position of each variant in the context of the three-dimensional structure of MT1 to link functional selectivity to structure. MT1 variant signaling profiles revealed three clusters characterized by (1) wild-type-like variants, (2) variants with selective defect of βarrestin-2 recruitment, and (3) severely defective variants on all pathways. Our structural analysis allows us to identify important regions for βarrestin-2 recruitment as well as for Gα12 and Gα15 activation. In addition to identifying MT1 domains differentially controlling the activation of the various signaling effectors, this study illustrates how natural variants can be used as tools to study the molecular mechanisms of receptor activation.
Fichier principal
Vignette du fichier
acsptsci.1c00157.pdf (3.68 Mo) Télécharger le fichier
Origine : Publication financée par une institution
licence : CC BY NC ND - Paternité - Pas d'utilisation commerciale - Pas de modification

Dates et versions

hal-03583044 , version 1 (06-06-2023)

Identifiants

Citer

Alan Hegron, Eunna Huh, Xavier Deupi, Badr Sokrat, Wenwen Gao, et al.. Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants. ACS Pharmacology & Translational Science, 2021, 4 (5), pp.1614-1627. ⟨10.1021/acsptsci.1c00157⟩. ⟨hal-03583044⟩
53 Consultations
11 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More