title: Structure of the human histamine H1 receptor complex with doxepin.
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.
authors.affiliation: Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Kyoto 606-8501, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Shimamura
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Shiroishi
authors.forename: Simone
authors.initials: S
authors.lastname: Weyand
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tsujimoto
authors.forename: Graeme
authors.initials: G
authors.lastname: Winter
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.forename: Takuya
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: So
authors.initials: S
authors.lastname: Iwata
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004316:Doxepin / Q000737:chemistry / Q000378:metabolism*; D006633:Histamine Antagonists / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007536:Isomerism; D008024:Ligands; D008958:Models, Molecular; D010710:Phosphates / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D050637:Receptors, Dopamine D3 / Q000737:chemistry; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D006633:Histamine Antagonists; D008024:Ligands; D010710:Phosphates; D018343:Receptors, Adrenergic, beta-2; D050637:Receptors, Dopamine D3; D011969:Receptors, Histamine H1; D004316:Doxepin