The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H1 receptor (H1R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H1R complex with doxepin, a first-generation H1R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp 4286.48, a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H1R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys 1915.39 and/or Lys 179ECL2, both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H1R antagonist specificity against H1R. The common antihistamines are antagonists of histamine H1 receptor (H1R), a G-protein-coupled receptor (GPCR) that is expressed in various tissues including airway, intestinal smooth muscle and brain. The X-ray crystal structure of human H1R in the presence of doxepin, a first-generation H1R antagonist, is now reported. It shows that the drug resides in a much deeper pocket than in other aminergic GPCR structures. Analysis of drug–protein interactions should facilitate the development of antihistamines that are more selective and less likely to cause side effects than those currently available.

Structure of the human histamine H1 receptor complex with doxepin