| Structural highlights
Function
OPRX_HUMAN G-protein coupled opioid receptor that functions as a receptor for the endogenous neuropeptide nociceptin. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling via G proteins mediates inhibition of adenylate cyclase activity and calcium channel activity. Arrestins modulate signaling via G proteins and mediate the activation of alternative signaling pathways that lead to the activation of MAP kinases. Plays a role in modulating nociception and the perception of pain. Plays a role in the regulation of locomotor activity by the neuropeptide nociceptin.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Opioids are effective analgesics, but their use is beset by serious side effects, including addiction and respiratory depression, which contribute to the ongoing opioid crisis. The human opioid system contains four opioid receptors (muOR, deltaOR, kappaOR, and NOPR) and a set of related endogenous opioid peptides (EOPs), which show distinct selectivity toward their respective opioid receptors (ORs). Despite being key to the development of safer analgesics, the mechanisms of molecular recognition and selectivity of EOPs to ORs remain unclear. Here, we systematically characterize the binding of EOPs to ORs and present five structures of EOP-OR-G(i) complexes, including beta-endorphin- and endomorphin-bound muOR, deltorphin-bound deltaOR, dynorphin-bound kappaOR, and nociceptin-bound NOPR. These structures, supported by biochemical results, uncover the specific recognition and selectivity of opioid peptides and the conserved mechanism of opioid receptor activation. These results provide a structural framework to facilitate rational design of safer opioid drugs for pain relief.
Structures of the entire human opioid receptor family.,Wang Y, Zhuang Y, DiBerto JF, Zhou XE, Schmitz GP, Yuan Q, Jain MK, Liu W, Melcher K, Jiang Y, Roth BL, Xu HE Cell. 2023 Jan 19;186(2):413-427.e17. doi: 10.1016/j.cell.2022.12.026. Epub 2023 , Jan 12. PMID:36638794[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Serhan CN, Fierro IM, Chiang N, Pouliot M. Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4. J Immunol. 2001 Mar 15;166(6):3650-4. doi: 10.4049/jimmunol.166.6.3650. PMID:11238602 doi:http://dx.doi.org/10.4049/jimmunol.166.6.3650
- ↑ Spampinato S, Di Toro R, Alessandri M, Murari G. Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells. Cell Mol Life Sci. 2002 Dec;59(12):2172-83. doi: 10.1007/s000180200016. PMID:12568343 doi:http://dx.doi.org/10.1007/s000180200016
- ↑ Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang XP, Trapella C, Guerrini R, Calo G, Roth BL, Cherezov V, Stevens RC. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature. 2012 May 16;485(7398):395-9. doi: 10.1038/nature11085. PMID:22596163 doi:10.1038/nature11085
- ↑ Zhang NR, Planer W, Siuda ER, Zhao HC, Stickler L, Chang SD, Baird MA, Cao YQ, Bruchas MR. Serine 363 is required for nociceptin/orphanin FQ opioid receptor (NOPR) desensitization, internalization, and arrestin signaling. J Biol Chem. 2012 Dec 7;287(50):42019-30. doi: 10.1074/jbc.M112.405696. Epub 2012, Oct 19. PMID:23086955 doi:http://dx.doi.org/10.1074/jbc.M112.405696
- ↑ Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC. ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett. 1994 Mar 14;341(1):33-8. doi: 10.1016/0014-5793(94)80235-1. PMID:8137918 doi:http://dx.doi.org/10.1016/0014-5793(94)80235-1
- ↑ Wang Y, Zhuang Y, DiBerto JF, Zhou XE, Schmitz GP, Yuan Q, Jain MK, Liu W, Melcher K, Jiang Y, Roth BL, Xu HE. Structures of the entire human opioid receptor family. Cell. 2023 Jan 19;186(2):413-427.e17. PMID:36638794 doi:10.1016/j.cell.2022.12.026
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