8EFO

PZM21-bound mu-opioid receptor-Gi complex

8EFO の概要

• エントリーDOI: 10.2210/pdb8efo/pdb
• EMDBエントリー: 28066 28069 28077 28085 28086 28088
• 分子名称: Mu-type opioid receptor, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• 機能のキーワード: mu-opioid receptor, g protein, fentanyl, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 240616.95

構造登録者

Zhuang, Y.,Wang, Y.,Guo, S.,Zhou, X.E.,Rao, Q.,He, X.,He, B.,Liu, J.,Zhou, Q.,Wang, X.,Liu, W.,Jiang, X.,Yang, D.,Chen, X.,Jiang, Y.,Jiang, H.,Shen, J.,Melcher, K.,Wang, M.,Xie, X.,Xu, H.E. (登録日: 2022-09-08, 公開日: 2022-11-09, 最終更新日: 2025-05-21)

主引用文献

Zhuang, Y.,Wang, Y.,He, B.,He, X.,Zhou, X.E.,Guo, S.,Rao, Q.,Yang, J.,Liu, J.,Zhou, Q.,Wang, X.,Liu, M.,Liu, W.,Jiang, X.,Yang, D.,Jiang, H.,Shen, J.,Melcher, K.,Chen, H.,Jiang, Y.,Cheng, X.,Wang, M.W.,Xie, X.,Xu, H.E.
Molecular recognition of morphine and fentanyl by the human mu-opioid receptor.
Cell, 185:4361-4375.e19, 2022

PubMed Abstract: Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of μ-opioid receptor (μOR). Here, we report structures of the human μOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of μOR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of μOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of μOR, which may facilitate rational design of next-generation analgesics.

PubMed: 36368306
DOI: 10.1016/j.cell.2022.09.041

実験手法

ELECTRON MICROSCOPY (2.8 Å)