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Molecular insights into the μ-opioid receptor biased signaling
- Source :
- Mol Cell
- Publication Year :
- 2021
-
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.
- Subjects :
- Binding Sites
Magnetic Resonance Spectroscopy
Protein Stability
Receptors, Opioid, mu
Molecular Dynamics Simulation
Ligands
Article
Analgesics, Opioid
Drug Partial Agonism
Mice
Structure-Activity Relationship
HEK293 Cells
Drug Design
Sf9 Cells
Animals
Computer-Aided Design
Humans
Protein Interaction Domains and Motifs
beta-Arrestins
Protein Binding
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Mol Cell
- Accession number :
- edsair.pmid..........9b18e2aa875b759a3b917a15c2b697aa