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

Autor: Qu Q; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.; Shanghai Stomatological Hospital, Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Department of Systems Biology for Medicine, Fudan University, Shanghai, China., Huang W; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Aydin D; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Computer Science, Stanford University, Stanford, CA, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA., Paggi JM; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Computer Science, Stanford University, Stanford, CA, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA., Seven AB; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA., Wang H; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA., Chakraborty S; Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, MO, USA.; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA., Che T; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.; Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA., DiBerto JF; Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA., Robertson MJ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA., Inoue A; Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan., Suomivuori CM; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Computer Science, Stanford University, Stanford, CA, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA., Roth BL; Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA., Majumdar S; Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, MO, USA. susrutam@wustl.edu.; Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA. susrutam@wustl.edu., Dror RO; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. ron.dror@stanford.edu.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. ron.dror@stanford.edu.; Department of Computer Science, Stanford University, Stanford, CA, USA. ron.dror@stanford.edu.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA. ron.dror@stanford.edu., Kobilka BK; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kobilka@stanford.edu., Skiniotis G; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2023 Apr; Vol. 19 (4), pp. 423-430. Date of Electronic Publication: 2022 Nov 21.
DOI: 10.1038/s41589-022-01208-y
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
Externí odkaz: