Structural analysis of the histamine H1 receptor

Mitsunori Shiroishi, Takuya Kobayashi

Research output: Chapter in Book/Report/Conference proceedingChapter

6 Citations (Scopus)


The crystal structure of the human histamine H1 receptor (H1R) has been determined in complex with its inverse agonist doxepin, a first-generation antihistamine. The crystal structure showed that doxepin sits deeply inside the ligand-binding pocket and predominantly interacts with residues highly conserved among other aminergic receptors. This binding mode is considered to result in the low selectivity of the first-generation antihistamines for H1R. The crystal structure also revealed the mechanism of receptor inactivation by the inverse agonist doxepin. On the other hand, the crystal structure elucidated the anion-binding site near the extracellular portion of the receptor. This site consists of residues not conserved among other aminergic receptors, which are specific for H1R. Docking simulation and biochemical experimentation demonstrated that a carboxyl group on the second-generation antihistamines interacts with the anion-binding site. These results imply that the anion-binding site is a key site for the development of highly selective antihistamine drugs.

Original languageEnglish
Title of host publicationHandbook of Experimental Pharmacology
PublisherSpringer New York LLC
Number of pages10
Publication statusPublished - 2017

Publication series

NameHandbook of Experimental Pharmacology
ISSN (Print)0171-2004
ISSN (Electronic)1865-0325

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology, Toxicology and Pharmaceutics(all)


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