9CM3

Cryo-EM structure of Gq-coupled FFA2 in complex with TUG-1375 and compound 187

これはPDB形式変換不可エントリーです。

9CM3 の概要

• エントリーDOI: 10.2210/pdb9cm3/pdb
• EMDBエントリー: 45738
• 分子名称: Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, scFv16, ... (9 entities in total)
• 機能のキーワード: gpcr, agonist, 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: 167954.80

構造登録者

Zhang, X.,Tikhonova, I.,Milligan, G.,Zhang, C. (登録日: 2024-07-12, 公開日: 2025-06-25, 最終更新日: 2025-08-13)

主引用文献

Zhang, X.,Guseinov, A.A.,Jenkins, L.,Valentini, A.,Marsango, S.,Schultz-Knudsen, K.,Ulven, T.,Rexen Ulven, E.,Tikhonova, I.G.,Milligan, G.,Zhang, C.
Allosteric modulation and biased signalling at free fatty acid receptor 2.
Nature, 643:1428-1438, 2025

PubMed Abstract: Free fatty acid receptor 2 (FFA2) is a G protein-coupled receptor (GPCR) that is a primary sensor for short-chain fatty acids produced by gut microbiota. Consequently, FFA2 is a promising drug target for immunometabolic disorders. Here we report cryogenic electronic microscopy structures of FFA2 in complex with two G proteins and three distinct classes of positive allosteric modulators (PAMs), and describe noncanonical activation mechanisms that involve conserved structural features of class A GPCRs. Two PAMs disrupt the E/DRY activation microswitch and stabilize the conformation of intracellular loop 2 by binding to lipid-facing pockets near the cytoplasmic side of the receptor. By contrast, the third PAM promotes the separation of transmembrane helices 6 and 7 by interacting with transmembrane helix 6 at the receptor-lipid interface. Molecular dynamic simulations and mutagenesis experiments confirm these noncanonical activation mechanisms. Furthermore, we demonstrate the molecular basis for the G versus G bias, which is due to distinct conformations of intracellular loop 2 stabilized by different PAMs. These findings provide a framework for the design of tailored GPCR modulators, with implications that extend beyond FFA2 to the broader field of GPCR drug discovery.

PubMed: 40533560
DOI: 10.1038/s41586-025-09186-6

実験手法

ELECTRON MICROSCOPY (3.06 Å)