8dzr | pdb_00008dzr
GR89,696 bound Kappa Opioid Receptor in complex with gustducin
Structural highlights
FunctionOPRK_HUMAN G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions.[1] [2] [3] [4] Publication Abstract from PubMedThe kappa-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. Ligand and G-protein selectivity in the kappa-opioid receptor.,Han J, Zhang J, Nazarova AL, Bernhard SM, Krumm BE, Zhao L, Lam JH, Rangari VA, Majumdar S, Nichols DE, Katritch V, Yuan P, Fay JF, Che T Nature. 2023 May;617(7960):417-425. doi: 10.1038/s41586-023-06030-7. Epub 2023 , May 3. PMID:37138078[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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