Structure of the human histamine H 1 receptor complex with doxepin

Tatsuro Shimamura, Mitsunori Shiroishi, Simone Weyand, Hirokazu Tsujimoto, Graeme Winter, Vsevolod Katritch, Ruben Abagyan, Vadim Cherezov, Wei Liu, Gye Won Han, Takuya Kobayashi, Raymond C. Stevens, So Iwata

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569 Scopus citations

Abstract

The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H 1 receptor (H 1 R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H 1 R complex with doxepin, a first-generation H 1 R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp-428 6.48, 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 H 1 R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys-191 5.39 and/or Lys-179 ECL2, 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 H 1 R antagonist specificity against H 1 R.

Original languageEnglish (US)
Pages (from-to)65-72
Number of pages8
JournalNature
Volume475
Issue number7354
DOIs
StatePublished - Jul 7 2011

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    Shimamura, T., Shiroishi, M., Weyand, S., Tsujimoto, H., Winter, G., Katritch, V., Abagyan, R., Cherezov, V., Liu, W., Han, G. W., Kobayashi, T., Stevens, R. C., & Iwata, S. (2011). Structure of the human histamine H 1 receptor complex with doxepin. Nature, 475(7354), 65-72. https://doi.org/10.1038/nature10236