7YIT

Molecular mechanism of biased signaling at the kappa opioid receptor

7YIT の概要

• エントリーDOI: 10.2210/pdb7yit/pdb
• 分子名称: Kappa-type opioid receptor, Nanobody39, Soluble cytochrome b562, ... (4 entities in total)
• 機能のキーワード: kappa opioid receptor, membrane protein, nalfurafine, opioids, membrane protein-inhibitor-immune system complex, membrane protein/inhibitor/immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 60825.38

構造登録者

Kim, K.,Che, T. (登録日: 2022-07-18, 公開日: 2023-04-12, 最終更新日: 2024-11-13)

主引用文献

El Daibani, A.,Paggi, J.M.,Kim, K.,Laloudakis, Y.D.,Popov, P.,Bernhard, S.M.,Krumm, B.E.,Olsen, R.H.J.,Diberto, J.,Carroll, F.I.,Katritch, V.,Wunsch, B.,Dror, R.O.,Che, T.
Molecular mechanism of biased signaling at the kappa opioid receptor.
Nat Commun, 14:1338-1338, 2023

PubMed Abstract: The κ-opioid receptor (KOR) has emerged as an attractive drug target for pain management without addiction, and biased signaling through particular pathways of KOR may be key to maintaining this benefit while minimizing side-effect liabilities. As for most G protein-coupled receptors (GPCRs), however, the molecular mechanisms of ligand-specific signaling at KOR have remained unclear. To better understand the molecular determinants of KOR signaling bias, we apply structure determination, atomic-level molecular dynamics (MD) simulations, and functional assays. We determine a crystal structure of KOR bound to the G protein-biased agonist nalfurafine, the first approved KOR-targeting drug. We also identify an arrestin-biased KOR agonist, WMS-X600. Using MD simulations of KOR bound to nalfurafine, WMS-X600, and a balanced agonist U50,488, we identify three active-state receptor conformations, including one that appears to favor arrestin signaling over G protein signaling and another that appears to favor G protein signaling over arrestin signaling. These results, combined with mutagenesis validation, provide a molecular explanation of how agonists achieve biased signaling at KOR.

PubMed: 36906681
DOI: 10.1038/s41467-023-37041-7

実験手法

X-RAY DIFFRACTION (3.3 Å)