7U2L

C5guano-uOR-Gi-scFv16

7U2L の概要

• エントリーDOI: 10.2210/pdb7u2l/pdb
• EMDBエントリー: 26314
• 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: 154114.84

構造登録者

Wang, H.,Qu, Q.,Skiniotis, G.,Kobilka, B. (登録日: 2022-02-24, 公開日: 2022-05-04, 最終更新日: 2024-11-06)

主引用文献

Faouzi, A.,Wang, H.,Zaidi, S.A.,DiBerto, J.F.,Che, T.,Qu, Q.,Robertson, M.J.,Madasu, M.K.,El Daibani, A.,Varga, B.R.,Zhang, T.,Ruiz, C.,Liu, S.,Xu, J.,Appourchaux, K.,Slocum, S.T.,Eans, S.O.,Cameron, M.D.,Al-Hasani, R.,Pan, Y.X.,Roth, B.L.,McLaughlin, J.P.,Skiniotis, G.,Katritch, V.,Kobilka, B.K.,Majumdar, S.
Structure-based design of bitopic ligands for the μ-opioid receptor.
Nature, 613:767-774, 2023

PubMed Abstract: Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site found in µOR and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp residue in the Na site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at G subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest G efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for G, G and G subtypes and arrestins, thus modulating their in vivo pharmacology.

PubMed: 36450356
DOI: 10.1038/s41586-022-05588-y

実験手法

ELECTRON MICROSCOPY (3.2 Å)