Downloads: 1473

Files in This Item:
File Description SizeFormat 
nature10236.pdf1.58 MBAdobe PDFView/Open
Title: Structure of the human histamine H1 receptor complex with doxepin.
Authors: Shimamura, Tatsuro  kyouindb  KAKEN_id
Shiroishi, Mitsunori
Weyand, Simone
Tsujimoto, Hirokazu
Winter, Graeme
Katritch, Vsevolod
Abagyan, Ruben
Cherezov, Vadim
Liu, Wei
Han, Gye Won
Kobayashi, Takuya  kyouindb  KAKEN_id
Stevens, Raymond C
Iwata, So  kyouindb  KAKEN_id
Author's alias: 小林, 拓也
Keywords: Structural biology
Drug discovery
Medical research
Issue Date: 7-Jul-2011
Publisher: Nature Publishing Group
Journal title: Nature
Volume: 475
Issue: 7354
Start page: 65
End page: 70
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.
Rights: © 2011 Nature Publishing Group, a division of Macmillan Publishers Limited.
This is not the published version. Please cite only the published version.
DOI(Published Version): 10.1038/nature10236
PubMed ID: 21697825
Appears in Collections:Journal Articles

Show full item record

Export to RefWorks

Export Format: 

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.