nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / G protein-coupled receptor activity / electron transport chain / cell junction / G alpha (i) signalling events / periplasmic space / electron transfer activity / iron ion binding / G protein-coupled receptor signaling pathway ...nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / G protein-coupled receptor activity / electron transport chain / cell junction / G alpha (i) signalling events / periplasmic space / electron transfer activity / iron ion binding / G protein-coupled receptor signaling pathway / heme binding / plasma membrane 類似検索 - 分子機能
ジャーナル: Nat Commun / 年: 2023 タイトル: Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding. 著者: Shota Suzuki / Kotaro Tanaka / Kouki Nishikawa / Hiroshi Suzuki / Atsunori Oshima / Yoshinori Fujiyoshi / 要旨: Hydroxycarboxylic acid receptors (HCA) are expressed in various tissues and immune cells. HCA2 and its agonist are thus important targets for treating inflammatory and metabolic disorders. Only ...Hydroxycarboxylic acid receptors (HCA) are expressed in various tissues and immune cells. HCA2 and its agonist are thus important targets for treating inflammatory and metabolic disorders. Only limited information is available, however, on the active-state binding of HCAs with agonists. Here, we present cryo-EM structures of human HCA2-Gi and HCA3-Gi signaling complexes binding with multiple compounds bound. Agonists were revealed to form a salt bridge with arginine, which is conserved in the HCA family, to activate these receptors. Extracellular regions of the receptors form a lid-like structure that covers the ligand-binding pocket. Although transmembrane (TM) 6 in HCAs undergoes dynamic conformational changes, ligands do not directly interact with amino acids in TM6, suggesting that indirect signaling induces a slight shift in TM6 to activate Gi proteins. Structural analyses of agonist-bound HCA2 and HCA3 together with mutagenesis and molecular dynamics simulation provide molecular insights into HCA ligand recognition and activation mechanisms.