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TitleInsights into distinct signaling profiles of the µOR activated by diverse agonists.
Journal, issue, pagesNat Chem Biol, Vol. 19, Issue 4, Page 423-430, Year 2023
Publish dateNov 21, 2022
AuthorsQianhui 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 /
PubMed AbstractDrugs 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 ...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.
External linksNat Chem Biol / PubMed:36411392
MethodsEM (single particle)
Resolution2.5 - 3.2 Å
Structure data

25612

7t2g

EMDB-25612, PDB-7t2g:
CryoEM structure of mu-opioid receptor - Gi protein complex bound to mitragynine pseudoindoxyl (MP)
Method: EM (single particle) / Resolution: 2.5 Å

25613

7t2h

EMDB-25613, PDB-7t2h:
CryoEM structure of mu-opioid receptor - Gi protein complex bound to lofentanil (LFT)
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-EIG:
Mitragynine pseudoindoxyl / Mitragynine pseudoindoxyl

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-HOH:
WATER / Water

ChemComp-EID:
Lofentanil / Lofentanil

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / GPCR / mu-opioid receptor / lofentanil (LFT) / mitragynine pseudoindoxyl (MP)

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