biostudies-literatureZhu CNIDA NIH HHSNational Institutes of HealthNIGMS NIH HHSCanadian Institutes of Health ResearchNIH HHSCIHR878-884https://www.ebi.ac.uk/biostudies/studies/S-EPMC6718349biostudies-literatureUnknown87(10)The G protein-coupled μ-opioid receptor (μ-OR) mediates the majority of analgesia effects for morphine and other pain relievers. Despite extensive studies of its structure and activation mechanisms, the inherently low maturation efficiency of μ-OR represents a major hurdle to understanding its function. Here we computationally designed μ-OR mutants with altered stability to probe the relationship between cell-surface targeting, signal transduction, and agonist efficacy. The stabilizing mutation T315Y enhanced μ-OR trafficking to the plasma membrane and significantly promoted the morphine-mediated inhibition of downstream signaling. In contrast, the destabilizing mutation R165Y led to intracellular retention of μ-OR and reduced the response to morphine stimulation. These findings suggest thProteinsStabilization of μ-opioid receptor facilitates its cellular translocation and signaling.PMC6718349GM123247R41 DA032293R01GM114015R01 GM114015R01 GM123247STTR 1R41DA032293CERC09Linton AHan QJi RRSamoshkin AFaison EMDokholyan NVConvertino MZhu CDiatchenko LfalseStabilization of μ-opioid receptor facilitates its cellular translocation and signaling.The G protein-coupled μ-opioid receptor (μ-OR) mediates the majority of analgesia effects for morphine and other pain relievers. Despite extensive studies of its structure and activation mechanisms, the inherently low maturation efficiency of μ-OR represents a major hurdle to understanding its function. Here we computationally designed μ-OR mutants with altered stability to probe the relationship between cell-surface targeting, signal transduction, and agonist efficacy. The stabilizing mutation T315Y enhanced μ-OR trafficking to the plasma membrane and significantly promoted the morphine-mediated inhibition of downstream signaling. In contrast, the destabilizing mutation R165Y led to intracellular retention of μ-OR and reduced the response to morphine stimulation. These findings suggest th2019-01-01T00:00:00Z2019 Oct2026-05-03T00:13:38.211Z2020-10-08T07:14:41ZS-EPMC67183493114121410.1002/prot.25751