Structure of the human histamine H1 receptor complex with doxepin. Nature 2011 Jun 22;475(7354):65-70
Date
06/24/2011Pubmed ID
21697825Pubmed Central ID
PMC3131495DOI
10.1038/nature10236Scopus ID
2-s2.0-79960070651 (requires institutional sign-in at Scopus site) 732 CitationsAbstract
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.
Author List
Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata SAuthor
Wei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Binding SitesCrystallography, X-Ray
Doxepin
Histamine Antagonists
Humans
Hydrophobic and Hydrophilic Interactions
Isomerism
Ligands
Models, Molecular
Phosphates
Protein Binding
Protein Conformation
Receptors, Adrenergic, beta-2
Receptors, Dopamine D3
Receptors, Histamine H1
Substrate Specificity
