Bias-inducing allosteric binding site in mu-opioid receptor signaling

Abstract

G-protein-biased agonism of the mu-opioid receptor (μ-OR) is emerging as a promising strategy in analgesia. A deep understanding of how biased agonists modulate and differentiate G-protein-coupled receptors (GPCR) signaling pathways and how this is transferred into the cell are open questions. Here, using extensive all-atom molecular dynamics simulations, we analyzed the binding recognition process and signaling effects of three prototype μ-OR agonists. Our suggested structural mechanism of biased signaling in μ-OR involves an allosteric sodium ion site, water networks, conformational rearrangements in conserved motifs and collective motions of loops and transmembrane helices. These analyses led us to highlight the relevance of a bias-inducing allosteric binding site in the understanding of μ-OR’s G-protein-biased signaling. These results also suggest a competitive equilibrium between the agonists and the allosteric sodium ion, where the bias-inducing allosteric binding site can be modulated by this ion or an agonist such as herkinorin. Notably, herkinorin arises as the archetype modulator of μ-OR and its interactive pattern could be used for screening efforts via protein–ligand interaction fingerprint (PLIF) studies. Article highlights Agonists and a sodium ion compete for the bias-inducing allosteric binding site that modulates signaling in mu-opioid receptors. Molecular dynamics simulations of the prototype μ-OR agonist suggest a competitive equilibrium involving the agonist and an allosteric sodium ion. Analysis of experimental data from the literature and molecular models provides the structural bases of biased agonism on μ-OR.

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

“…This process highlights the most important movements in a protein during the simulation. Using this analytical technique, Marmolejo-Valencia et al studied the biased signaling mechanism of the μ-opioid receptor (μ-OR) [ 24 ]. The impact of biased agonists on information transmission in the μ-OR’s intracellular backbone was mainly observed in the helix 8 (H8) and ICL3 loop movements by FMA.…”

Intracellular pocket conformations determine signaling efficacy through the μ opioid receptor

“…The sodium binding site 40 , which houses the cation in inactive conformations, comprises D116 2.50 , S156 3.39 , N330 7.45 , S331 7.46 , and N334 7.49 . The site allosterically communicates with the orthosteric site and the intracellular pocket 2,34,40,41 . Ligand-interactions with D149 3.32 and Y150 3.33 in the orthosteric site affect the position of the neighboring residue N152 3.35 .…”