Ligand and G-protein selectivity in the κ-opioid receptor.

Autor: Han J; Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USA.; Center for Clinical Pharmacology, University of Health Sciences and Pharmacy in St Louis and Washington University School of Medicine, St Louis, MO, USA., Zhang J; Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA.; Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St Louis, MO, USA.; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Nazarova AL; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.; Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA., Bernhard SM; Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USA.; Center for Clinical Pharmacology, University of Health Sciences and Pharmacy in St Louis and Washington University School of Medicine, St Louis, MO, USA., Krumm BE; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA., Zhao L; Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USA., Lam JH; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.; Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA., Rangari VA; Center for Clinical Pharmacology, University of Health Sciences and Pharmacy in St Louis and Washington University School of Medicine, St Louis, MO, USA., Majumdar S; Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USA.; Center for Clinical Pharmacology, University of Health Sciences and Pharmacy in St Louis and Washington University School of Medicine, St Louis, MO, USA.; Washington University Pain Center, Washington University in St Louis, St Louis, MO, USA., Nichols DE; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA., Katritch V; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.; Department of Chemistry, University of Southern California, Los Angeles, CA, USA.; Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA., Yuan P; Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA.; Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St Louis, MO, USA.; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Fay JF; Department of Biochemistry and Molecular Biology, University of Maryland Baltimore, Baltimore, MD, USA. jfay@som.umaryland.edu., Che T; Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USA. taoche@wustl.edu.; Center for Clinical Pharmacology, University of Health Sciences and Pharmacy in St Louis and Washington University School of Medicine, St Louis, MO, USA. taoche@wustl.edu.; Washington University Pain Center, Washington University in St Louis, St Louis, MO, USA. taoche@wustl.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2023 May; Vol. 617 (7960), pp. 417-425. Date of Electronic Publication: 2023 May 03.
DOI: 10.1038/s41586-023-06030-7
Abstrakt: The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders 1 . However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects 2 . The initiation of KOR signalling requires the G i/o -family proteins including the conventional (G i1 , G i2 , G i3 , G oA and G oB ) and nonconventional (G z and G g ) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers-G i1 , G oA , G z and G g -using cryo-electron microscopy. The KOR-G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR-G-protein interactions as well as key elements governing G i/o -family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.
(© 2023. The Author(s).)
Databáze: MEDLINE
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