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Papers of the Week

Papers: 25 May 2019 - 31 May 2019

Pharmacology/Drug Development

2019 Oct




Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling.


Zhu C, Han Q, Samoshkin A, Convertino M, Linton A, Faison EM, Ji R-R, Diatchenko L, Dokholyan NV
Proteins. 2019 Oct; 87(10):878-884.
PMID: 31141214.


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 that μ-OR stability is an important factor in regulating receptor signaling and provide a viable avenue to improve the efficacy of analgesics. This article is protected by copyright. All rights reserved.