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CryoEM structure of delta opioid receptor bound to G proteins and a full bitopic agonist
Structural highlights
FunctionOPRD_HUMAN G-protein coupled receptor that functions as a receptor for endogenous enkephalins and for a subset of other opioids. 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 and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine.[1] [2] [3] Publication Abstract from PubMedChronic pain and opioid overdose deaths highlight the need for non-addictive analgesics with novel mechanisms. The delta opioid receptor (deltaOR) is a promising target, as it lacks the respiratory depression associated with micro opioid receptor (microOR) agonists. However, early deltaOR full agonists caused seizures, limiting their clinical use. Partial deltaOR agonists may offer more controlled receptor activation than full agonists, but their development has been hindered by uncertainty regarding the molecular mechanism of partial agonism. Here we show that C6-Quino, a bitopic ligand developed through structure-based design, acts as a selective deltaOR partial agonist. Functional studies reveal that C6-Quino shows differential activity at G-protein and arrestin pathways and interacts with the sodium binding pocket, confirmed through cryo-EM analysis. C6-Quino demonstrates oral activity, analgesic activity in chronic pain models without causing deltaOR-related seizures and microOR-related adverse effects which have limited opioid usage in recent times. This discovery outlines a new strategy for developing deltaOR-targeted analgesics and provides a framework for optimizing signaling profiles of other Class A GPCRs. Structure-guided design of partial agonists at an opioid receptor.,Varga BR, Bernhard SM, El Daibani A, Zaidi SA, Lam JH, Aguilar J, Appourchaux K, Nazarova AL, Kouvelis A, Shinouchi R, Hammond HR, Eans SO, Weinreb V, Margolis EB, Fay JF, Huang XP, Pradhan A, Katritch V, McLaughlin JP, Majumdar S, Che T Nat Commun. 2025 Mar 13;16(1):2518. doi: 10.1038/s41467-025-57734-5. PMID:40082451[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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