8T3O

Cryo-EM structure of the TUG-891 bound FFA4-Gq complex

8T3O の概要

• エントリーDOI: 10.2210/pdb8t3o/pdb
• EMDBエントリー: 41007
• 分子名称: Free fatty acid receptor 4, 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, ... (8 entities in total)
• 機能のキーワード: gpcr, complex, 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: 134188.45

構造登録者

Zhang, X.,Tikhonova, I.,Milligan, G.,Zhang, C. (登録日: 2023-06-07, 公開日: 2024-01-17)

主引用文献

Zhang, X.,Guseinov, A.A.,Jenkins, L.,Li, K.,Tikhonova, I.G.,Milligan, G.,Zhang, C.
Structural basis for the ligand recognition and signaling of free fatty acid receptors.
Sci Adv, 10:eadj2384-eadj2384, 2024

PubMed Abstract: Free fatty acid receptors 1 to 4 (FFA1 to FFA4) are class A G protein-coupled receptors (GPCRs). FFA1 to FFA3 share substantial sequence similarity, whereas FFA4 is unrelated. However, FFA1 and FFA4 are activated by long-chain fatty acids, while FFA2 and FFA3 respond to short-chain fatty acids generated by intestinal microbiota. FFA1, FFA2, and FFA4 are potential drug targets for metabolic and inflammatory conditions. Here, we determined the active structures of FFA1 and FFA4 bound to docosahexaenoic acid, FFA4 bound to the synthetic agonist TUG-891, and butyrate-bound FFA2, each complexed with an engineered heterotrimeric G protein (miniG), by cryo-electron microscopy. Together with computational simulations and mutagenesis studies, we elucidated the similarities and differences in the binding modes of fatty acid ligands to their respective GPCRs. Our findings unveiled distinct mechanisms of receptor activation and G protein coupling. We anticipate that these outcomes will facilitate structure-based drug development and underpin future research on this group of GPCRs.

PubMed: 38198545
DOI: 10.1126/sciadv.adj2384

実験手法

ELECTRON MICROSCOPY (3.06 Å)