9CGK

CryoEM structure of delta opioid receptor bound to G proteins and a full bitopic agonist

これはPDB形式変換不可エントリーです。

9CGK の概要

• エントリーDOI: 10.2210/pdb9cgk/pdb
• EMDBエントリー: 45582
• 分子名称: Delta-type opioid receptor, ScFv16 protein, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• 機能のキーワード: gpcr, delta opioid receptor, bitopic ligand, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 146460.70

構造登録者

Fay, J.F.,Che, T. (登録日: 2024-06-29, 公開日: 2025-04-02)

主引用文献

Varga, B.R.,Bernhard, S.M.,El Daibani, A.,Zaidi, S.A.,Lam, J.H.,Aguilar, J.,Appourchaux, K.,Nazarova, A.L.,Kouvelis, A.,Shinouchi, R.,Hammond, H.R.,Eans, S.O.,Weinreb, V.,Margolis, E.B.,Fay, J.F.,Huang, X.P.,Pradhan, A.,Katritch, V.,McLaughlin, J.P.,Majumdar, S.,Che, T.
Structure-guided design of partial agonists at an opioid receptor.
Nat Commun, 16:2518-2518, 2025

PubMed Abstract: Chronic pain and opioid overdose deaths highlight the need for non-addictive analgesics with novel mechanisms. The δ opioid receptor (δOR) is a promising target, as it lacks the respiratory depression associated with µ opioid receptor (µOR) agonists. However, early δOR full agonists caused seizures, limiting their clinical use. Partial δOR 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 δOR 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 δOR-related seizures and µOR-related adverse effects which have limited opioid usage in recent times. This discovery outlines a new strategy for developing δOR-targeted analgesics and provides a framework for optimizing signaling profiles of other Class A GPCRs.

PubMed: 40082451
DOI: 10.1038/s41467-025-57734-5

実験手法

ELECTRON MICROSCOPY (2.62 Å)