Structural insights into the agonists binding and receptor selectivity of human histamine H 4 receptor.

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.