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- Title
Structure of the human histamine H<sub>1</sub> receptor complex with doxepin.
- Authors
Shimamura, Tatsuro; Shiroishi, Mitsunori; Weyand, Simone; Tsujimoto, Hirokazu; Winter, Graeme; Katritch, Vsevolod; Abagyan, Ruben; Cherezov, Vadim; Wei Liu; Han, Gye Won; Kobayashi, Takuya; Stevens, Raymond C.; Iwata, So
- Abstract
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.
- Publication
Nature, 2011, Vol 475, Issue 7354, p65
- ISSN
0028-0836
- Publication type
Academic Journal
- DOI
10.1038/nature10236