TY - JOUR
T1 - Insights into distinct signaling profiles of the µOR activated by diverse agonists
AU - Qu, Qianhui
AU - Huang, Weijiao
AU - Aydin, Deniz
AU - Paggi, Joseph M.
AU - Seven, Alpay B.
AU - Wang, Haoqing
AU - Chakraborty, Soumen
AU - Che, Tao
AU - DiBerto, Jeffrey F.
AU - Robertson, Michael J.
AU - Inoue, Asuka
AU - Suomivuori, Carl Mikael
AU - Roth, Bryan L.
AU - Majumdar, Susruta
AU - Dror, Ron O.
AU - Kobilka, Brian K.
AU - Skiniotis, Georgios
N1 - Funding Information:
This work was supported by the Swiss National Science Foundation Early Postdoctoral Mobility grant no. P2ELP3_187989 (D.A.); the European Molecular Biology Organization Long-Term Fellowship grant no. ALTF 544-2019 (D.A.); a Stanford Graduate Fellowship (J.M.P.); the Human Frontier Science Program Long-Term Fellowship grant no. LT000916/2018-L (C.-M.S.); the National Institutes of Health grants no. R01GM127359 (R.O.D.), no. DA045884 (S.M.) and no. R37DA036246 (B.K.K. and G.S.); and the Mathers Foundation (G.S. and B.K.K.). B.K.K. is a Chan Zuckerberg Biohub Investigator. An award of computer time was provided by the INCITE program. This research used resources of the Oak Ridge Leadership Computing Facility, which is a US Department of Energy Office of Science User Facility supported under contract no. DE-AC05-00OR22725. A.I. was funded by grant nos. PRIME 19gm5910013, LEAP 19gm0010004 and BINDS JP20am0101095 from the Japan Agency for Medical Research and Development (AMED); grant nos. KAKENHI 21H04791 and 21H05113 from the Japan Society for the Promotion of Science (JSPS); and JST Moonshot Research and Development Program grant no. JPMJMS2023 from Japan Science and Technology Agency (JST). We thank F. M. N. Kadji, K. Sato, Y. Sugamura and A. Inoue at Tohoku University for plasmid construction and the cell-based GPCR assays; and Y. Laloudakis, S. Hollingsworth and N. Latorraca for helpful discussions.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022
Y1 - 2022
N2 - 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.]
AB - 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.]
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U2 - 10.1038/s41589-022-01208-y
DO - 10.1038/s41589-022-01208-y
M3 - Article
C2 - 36411392
AN - SCOPUS:85142395650
SN - 1552-4450
JO - Nature Chemical Biology
JF - Nature Chemical Biology
ER -