7XTQ

Cryo-EM structure of the R399-bound GPBAR-Gs complex

7XTQ の概要

• エントリーDOI: 10.2210/pdb7xtq/pdb
• EMDBエントリー: 33452
• 分子名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, 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, gpbar, complex, bile acid, 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: 141107.84

構造登録者

Ma, L.,Yang, F.,Wu, X.,Mao, C.,Sun, J.,Yu, X.,Zhang, Y.,Zhang, P. (登録日: 2022-05-17, 公開日: 2022-07-06, 最終更新日: 2024-10-09)

主引用文献

Ma, L.,Yang, F.,Wu, X.,Mao, C.,Guo, L.,Miao, T.,Zang, S.K.,Jiang, X.,Shen, D.D.,Wei, T.,Zhou, H.,Wei, Q.,Li, S.,Shu, Q.,Feng, S.,Jiang, C.,Chu, B.,Du, L.,Sun, J.P.,Yu, X.,Zhang, Y.,Zhang, P.
Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity.
Proc.Natl.Acad.Sci.USA, 119:e2117054119-e2117054119, 2022

PubMed Abstract: The G protein-coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver-bile acid-microbiota-organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for β-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR-β-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.

PubMed: 35858343
DOI: 10.1073/pnas.2117054119

実験手法

ELECTRON MICROSCOPY (3.2 Å)