Structural and Dynamic Insights into the Activation of the μ-opioid Receptor by an Allosteric Modulator

Abstract

The μ opioid receptor (MOR) is a G protein-coupled receptor that plays a crucial role in analgesia. We used solution NMR spectroscopy to investigate the activation mechanism of MOR in the presence of an allosteric modulator, BMS-986122, and identified that MOR exists in a dynamic equilibrium among three distinct conformations with different levels of activity. BMS-986122 binds to the transmembrane domain of MOR and stabilizes the fully active conformation of MOR by preventing the closure of the transmembrane helix 6. These findings may contribute to the development of novel analgesics with improved efficacy.