1. Molecular insights into the biased signaling mechanism of the μ-opioid receptor.
- Author
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Cong X, Maurel D, Déméné H, Vasiliauskaité-Brooks I, Hagelberger J, Peysson F, Saint-Paul J, Golebiowski J, Granier S, and Sounier R
- Subjects
- Analgesics, Opioid chemistry, Animals, Binding Sites, Computer-Aided Design, Drug Design, Drug Partial Agonism, HEK293 Cells, Humans, Ligands, Mice, Protein Binding, Protein Interaction Domains and Motifs, Protein Stability, Receptors, Opioid, mu agonists, Receptors, Opioid, mu genetics, Receptors, Opioid, mu metabolism, Sf9 Cells, Structure-Activity Relationship, beta-Arrestins genetics, beta-Arrestins metabolism, Analgesics, Opioid pharmacology, Magnetic Resonance Spectroscopy, Molecular Dynamics Simulation, Signal Transduction drug effects
- Abstract
GPCR functional selectivity opens new opportunities for the design of safer drugs. Ligands orchestrate GPCR signaling cascades by modulating the receptor conformational landscape. Our study provides insights into the dynamic mechanism enabling opioid ligands to preferentially activate the G protein over the β-arrestin pathways through the μ-opioid receptor (μOR). We combine functional assays in living cells, solution NMR spectroscopy, and enhanced-sampling molecular dynamic simulations to identify the specific μOR conformations induced by G protein-biased agonists. In particular, we describe the dynamic and allosteric communications between the ligand-binding pocket and the receptor intracellular domains, through conserved motifs in class A GPCRs. Most strikingly, the biased agonists trigger μOR conformational changes in the intracellular loop 1 and helix 8 domains, which may impair β-arrestin binding or signaling. The findings may apply to other GPCR families and provide key molecular information that could facilitate the design of biased ligands., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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