Structural Analysis of the Histamine H1Receptor.
The crystal structure of the human histamine H1receptor (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.
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. shiroish@phar.kyushu-u.ac.jp.|Platform for Drug Discovery, Informatics and Structural Life Science, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan. shiroish@phar.kyushu-u.ac.jp.
Mitsunori
M
Shiroishi
Platform for Drug Discovery, Informatics and Structural Life Science, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.|Department of Medical Chemistry and Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.|Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
Takuya
T
Kobayashi
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D004316:Doxepin / Q000737:chemistry / Q000494:pharmacology; D006632:Histamine / Q000737:chemistry / Q000378:metabolism; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism
D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D004316:Doxepin; D006632:Histamine
Crystal structure; Doxepin; First-generation antihistamines; Histamine H1 receptor; Receptor inactivation mechanism; Receptor selectivity of antihistamines