7T2G

CryoEM structure of mu-opioid receptor - Gi protein complex bound to mitragynine pseudoindoxyl (MP)

7T2G の概要

• エントリーDOI: 10.2210/pdb7t2g/pdb
• EMDBエントリー: 25612
• 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, ... (7 entities in total)
• 機能のキーワード: gpcr, mu-opioid receptor, lofentanil (lft), mitragynine pseudoindoxyl (mp), membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 142258.90

構造登録者

Seven, A.B.,Qu, Q.,Robertson, M.J.,Wang, H.,Kobilka, B.K.,Skiniotis, G. (登録日: 2021-12-04, 公開日: 2022-12-07, 最終更新日: 2024-11-06)

主引用文献

Qu, Q.,Huang, W.,Aydin, D.,Paggi, J.M.,Seven, A.B.,Wang, H.,Chakraborty, S.,Che, T.,DiBerto, J.F.,Robertson, M.J.,Inoue, A.,Suomivuori, C.M.,Roth, B.L.,Majumdar, S.,Dror, R.O.,Kobilka, B.K.,Skiniotis, G.
Insights into distinct signaling profiles of the mu OR activated by diverse agonists.
Nat.Chem.Biol., 2022

PubMed Abstract: Drugs targeting the μ-opioid receptor (μOR) are the most effective analgesics available but are also associated with fatal respiratory depression through a pathway that remains unclear. Here we investigated the mechanistic basis of action of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two μOR agonists with different safety profiles. LFT, one of the most lethal opioids, and MP, a kratom plant derivative with reduced respiratory depression in animal studies, exhibited markedly different efficacy profiles for G protein subtype activation and β-arrestin recruitment. Cryo-EM structures of μOR-Gi1 complex with MP (2.5 Å) and LFT (3.2 Å) revealed that the two ligands engage distinct subpockets, and molecular dynamics simulations showed additional differences in the binding site that promote distinct active-state conformations on the intracellular side of the receptor where G proteins and β-arrestins bind. These observations highlight how drugs engaging different parts of the μOR orthosteric pocket can lead to distinct signaling outcomes.

PubMed: 36411392
DOI: 10.1038/s41589-022-01208-y

実験手法

ELECTRON MICROSCOPY (2.5 Å)