8IKH

Cryo-EM structure of human receptor with G proteins

8IKH の概要

• エントリーDOI: 10.2210/pdb8ikh/pdb
• EMDBエントリー: 35512
• 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: membrane protein, complex, allosteric modulator
• 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: 151595.20

構造登録者

Shen, S.Y.,Shao, Z.H. (登録日: 2023-02-28, 公開日: 2024-06-05, 最終更新日: 2024-07-17)

主引用文献

Shen, S.,Wu, C.,Lin, G.,Yang, X.,Zhou, Y.,Zhao, C.,Miao, Z.,Tian, X.,Wang, K.,Yang, Z.,Liu, Z.,Guo, N.,Li, Y.,Xia, A.,Zhou, P.,Liu, J.,Yan, W.,Ke, B.,Yang, S.,Shao, Z.
Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1.
Proc.Natl.Acad.Sci.USA, 121:e2321532121-e2321532121, 2024

PubMed Abstract: is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and β-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.

PubMed: 38830102
DOI: 10.1073/pnas.2321532121

実験手法

ELECTRON MICROSCOPY (3.3 Å)