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Insights into distinct signaling profiles of the µOR activated by diverse agonists

Qianhui Qu1,2,3, Weijiao Huang1, Deniz Aydin1,2,4,5

  • 1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

Nature Chemical Biology
|November 21, 2022
PubMed

Insights

Lethal opioids and safer kratom derivatives activate the μ-opioid receptor (μOR) differently. Distinct binding interactions explain varying G protein and β-arrestin signaling, impacting respiratory depression safety.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Structural Biology

Background:

  • Opioids targeting the μ-opioid receptor (μOR) are effective analgesics but cause fatal respiratory depression via unknown mechanisms.
  • Understanding μOR signaling diversity is crucial for developing safer pain therapeutics.

Purpose of the Study:

  • To investigate the mechanistic basis for the differing safety profiles of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two μOR agonists.
  • To elucidate how distinct ligand interactions within the μOR orthosteric pocket influence downstream signaling pathways.

Main Methods:

  • Utilized cryo-electron microscopy (cryo-EM) to determine the structures of μOR-Gi1 complexes bound to MP and LFT.
  • Employed molecular dynamics (MD) simulations to analyze ligand-induced conformational changes in the μOR.
  • Assessed G protein subtype activation and β-arrestin recruitment efficacy for both ligands.

Main Results:

  • LFT and MP exhibited markedly different efficacy profiles for G protein and β-arrestin signaling.
  • Cryo-EM structures revealed that LFT and MP bind to distinct subpockets within the μOR orthosteric site.
  • MD simulations identified unique differences in the μOR binding site, promoting distinct active-state conformations affecting intracellular interactions.

Conclusions:

  • The distinct binding modes of LFT and MP within the μOR orthosteric pocket lead to divergent signaling outcomes.
  • These findings provide a structural and mechanistic basis for the differential safety profiles of μOR agonists.
  • This knowledge can guide the design of novel analgesics with reduced risk of respiratory depression.

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