Abstract
Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H(4) receptor (H(4)R) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the H(4)R-G(q) complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe344(7.39), which, in turn, form the "aromatic slot". The results provide insights into the molecular underpinnings of the agonism of H(4)R and subtype selectivity of histamine receptors, and show that the H(4)R structures may be valuable in rational drug design of drugs targeting the H(4)R.