7SBF

PZM21 bound Mu Opioid Receptor-Gi Protein Complex

7SBF の概要

• エントリーDOI: 10.2210/pdb7sbf/pdb
• EMDBエントリー: 24978
• 分子名称: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, 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, 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: 169217.50

構造登録者

Huang, W.,Qu, Q.,Wang, H.,Skiniotis, G.,Kobilka, B. (登録日: 2021-09-24, 公開日: 2022-04-20, 最終更新日: 2025-05-28)

主引用文献

Wang, H.,Hetzer, F.,Huang, W.,Qu, Q.,Meyerowitz, J.,Kaindl, J.,Hubner, H.,Skiniotis, G.,Kobilka, B.K.,Gmeiner, P.
Structure-Based Evolution of G Protein-Biased mu-Opioid Receptor Agonists.
Angew.Chem.Int.Ed.Engl., 61:e202200269-e202200269, 2022

PubMed Abstract: The μ-opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well as through β-arrestin recruitment. μOR agonists that are biased towards G protein signaling pathways demonstrate diminished side effects. PZM21, discovered by computational docking, is a G protein biased μOR agonist. Here we report the cryoEM structure of PZM21 bound μOR in complex with G protein. Structure-based evolution led to multiple PZM21 analogs with more pronounced G protein bias and increased lipophilicity to improve CNS penetration. Among them, FH210 shows extremely low potency and efficacy for arrestin recruitment. We further determined the cryoEM structure of FH210 bound to μOR in complex with G protein and confirmed its expected binding pose. The structural and pharmacological studies reveal a potential mechanism to reduce β-arrestin recruitment by the μOR, and hold promise for developing next-generation analgesics with fewer adverse effects.

PubMed: 35385593
DOI: 10.1002/anie.202200269

実験手法

ELECTRON MICROSCOPY (2.9 Å)