Structure of the human histamine H1 receptor complex with doxepin.

• Shimamura, Tatsuro

• Shiroishi, Mitsunori

• Weyand, Simone

• Tsujimoto, Hirokazu

• Winter, Graeme

• Katritch, Vsevolod

• Abagyan, Ruben

• Cherezov, Vadim

• Liu, Wei

• 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 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.

Journal

• Nature

  Nature 475 (7354), 65-70, 2011-07-07

  Nature Publishing Group

Keywords

• Structural biology
• Drug discovery
• Biochemistry
• Medical research
• Binding Sites
• Crystallography, X-Ray
• Doxepin/chemistry
• Doxepin/metabolism
• Histamine Antagonists/chemistry
• Histamine Antagonists/metabolism
• Humans
• Hydrophobic and Hydrophilic Interactions
• Isomerism
• Ligands
• Models, Molecular
• Phosphates/chemistry
• Phosphates/metabolism
• Protein Binding
• Protein Conformation
• Receptors, Adrenergic, beta-2/chemistry
• Receptors, Dopamine D3/chemistry
• Receptors, Histamine H1/chemistry
• Receptors, Histamine H1/metabolism
• Substrate Specificity

Details

• CRID: 1050564285688052096
• NII Article ID: 120004225543
• NII Book ID: AA00752384
• ISSN: 00280836
• HANDLE: 2433/156845
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles