8K9L

Full agonist- and positive allosteric modulator-bound mu-type opioid receptor-G protein complex

8K9L の概要

• エントリーDOI: 10.2210/pdb8k9l/pdb
• EMDBエントリー: 36990
• 関連するBIRD辞書のPRD_ID: PRD_002308
• 分子名称: Soluble cytochrome b562,Mu-type opioid receptor,Mu-type opioid receptor, DAMGO, G protein subunit alpha i3, ... (7 entities in total)
• 機能のキーワード: signaling protein
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 166733.27

構造登録者

Hisano, T.,Uchikubo-Kamo, T.,Shirouzu, M.,Imai, S.,Kaneko, S.,Shimada, I. (登録日: 2023-08-01, 公開日: 2024-05-29, 最終更新日: 2024-10-23)

主引用文献

Kaneko, S.,Imai, S.,Uchikubo-Kamo, T.,Hisano, T.,Asao, N.,Shirouzu, M.,Shimada, I.
Structural and dynamic insights into the activation of the mu-opioid receptor by an allosteric modulator.
Nat Commun, 15:3544-3544, 2024

PubMed Abstract: G-protein-coupled receptors (GPCRs) play pivotal roles in various physiological processes. These receptors are activated to different extents by diverse orthosteric ligands and allosteric modulators. However, the mechanisms underlying these variations in signaling activity by allosteric modulators remain largely elusive. Here, we determine the three-dimensional structure of the μ-opioid receptor (MOR), a class A GPCR, in complex with the G protein and an allosteric modulator, BMS-986122, using cryogenic electron microscopy. Our results reveal that BMS-986122 binding induces changes in the map densities corresponding to R167 and Y254, key residues in the structural motifs conserved among class A GPCRs. Nuclear magnetic resonance analyses of MOR in the absence of the G protein reveal that BMS-986122 binding enhances the formation of the interaction between R167 and Y254, thus stabilizing the fully-activated conformation, where the intracellular half of TM6 is outward-shifted to allow for interaction with the G protein. These findings illuminate that allosteric modulators like BMS-986122 can potentiate receptor activation through alterations in the conformational dynamics in the core region of GPCRs. Together, our results demonstrate the regulatory mechanisms of GPCRs, providing insights into the rational development of therapeutics targeting GPCRs.

PubMed: 38740791
DOI: 10.1038/s41467-024-47792-6

実験手法

ELECTRON MICROSCOPY (3.05 Å)