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

Qianhui Qu, Weijiao Huang, Deniz Aydin, Joseph M. Paggi, Alpay B. Seven, Haoqing Wang, Soumen Chakraborty, Tao Che, Jeffrey F. DiBerto, Michael J. Robertson, Asuka Inoue, Carl Mikael Suomivuori, Bryan L. Roth, Susruta Majumdar, Ron O. Dror, Brian K. Kobilka, Georgios Skiniotis

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


Drugs targeting the μ-opioid receptor (μOR) are the most effective analgesics available but are also associated with fatal respiratory depression through a pathway that remains unclear. Here we investigated the mechanistic basis of action of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two μOR agonists with different safety profiles. LFT, one of the most lethal opioids, and MP, a kratom plant derivative with reduced respiratory depression in animal studies, exhibited markedly different efficacy profiles for G protein subtype activation and β-arrestin recruitment. Cryo-EM structures of μOR-Gi1 complex with MP (2.5 Å) and LFT (3.2 Å) revealed that the two ligands engage distinct subpockets, and molecular dynamics simulations showed additional differences in the binding site that promote distinct active-state conformations on the intracellular side of the receptor where G proteins and β-arrestins bind. These observations highlight how drugs engaging different parts of the μOR orthosteric pocket can lead to distinct signaling outcomes. [Figure not available: see fulltext.]

Original languageEnglish
JournalNature Chemical Biology
Publication statusAccepted/In press - 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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