Ligand and G Protein Selectivity in Kappa Opioid Receptor Revealed by Structural Pharmacology [ASPET 2023 Annual Meeting Abstract - Central Nervous System Pharmacology - Neuropharmacology]

Abstract ID 18996

Poster Board 573

The kappa opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders. The development of KOR analgesics, however, has been hindered by the hallucinogenic side effects mediated by KOR signaling. The initiation of KOR signaling requires the Gi/o family proteins. However, how hallucinogens exert their actions via KOR and how KOR determines the G protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in complex with G protein heterotrimers by cryo-electron microscopy (Cryo-EM). Comparisons of these structures reveal molecular determinants critical for KOR-G protein interactions as well as key elements governing Gi/o family subtype selectivity and KOR ligand selectivity. These results provide novel insights into the actions of opioids and G protein-coupling specificity at KOR and establish a foundation to explore the therapeutic potential of pathway-selective agonists of KOR.

Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics

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