Structure of the human histamine H 1 receptor complex with doxepin

Tatsuro Shimamura, Mitsunori Shiroishi, Simone Weyand, Hirokazu Tsujimoto, Graeme Winter, Vsevolod Katritch, Ruben Abagyan, Vadim Cherezov, Wei Liu, Gye Won Han, Takuya Kobayashi, Raymond C. Stevens, So Iwata

研究成果: ジャーナルへの寄稿記事

542 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)65-72
ページ数8
ジャーナルNature
475
発行部数7354
DOI
出版物ステータス出版済み - 7 7 2011

Fingerprint

Doxepin
Histamine
Anions
Hypersensitivity
Biogenic Amines
G-Protein-Coupled Receptors
Phosphates
Pharmacology
Ions
Ligands
Inflammation
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • General

これを引用

Shimamura, T., Shiroishi, M., Weyand, S., Tsujimoto, H., Winter, G., Katritch, V., ... Iwata, S. (2011). Structure of the human histamine H 1 receptor complex with doxepin. Nature, 475(7354), 65-72. https://doi.org/10.1038/nature10236

Structure of the human histamine H 1 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.

:: Nature, 巻 475, 番号 7354, 07.07.2011, p. 65-72.

研究成果: ジャーナルへの寄稿記事

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, S 2011, 'Structure of the human histamine H 1 receptor complex with doxepin', Nature, 巻. 475, 番号 7354, pp. 65-72. https://doi.org/10.1038/nature10236
Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V その他. Structure of the human histamine H 1 receptor complex with doxepin. Nature. 2011 7 7;475(7354):65-72. https://doi.org/10.1038/nature10236
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. / Structure of the human histamine H 1 receptor complex with doxepin. :: Nature. 2011 ; 巻 475, 番号 7354. pp. 65-72.
@article{405f3e32807d4699b405278d9deb1671,
title = "Structure of the human histamine H 1 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.",
author = "Tatsuro Shimamura and Mitsunori Shiroishi and Simone Weyand and Hirokazu Tsujimoto and Graeme Winter and Vsevolod Katritch and Ruben Abagyan and Vadim Cherezov and Wei Liu and Han, {Gye Won} and Takuya Kobayashi and Stevens, {Raymond C.} and So Iwata",
year = "2011",
month = "7",
day = "7",
doi = "10.1038/nature10236",
language = "English",
volume = "475",
pages = "65--72",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7354",

}

TY - JOUR

T1 - Structure of the human histamine H 1 receptor complex with doxepin

AU - Shimamura, Tatsuro

AU - Shiroishi, Mitsunori

AU - Weyand, Simone

AU - Tsujimoto, Hirokazu

AU - Winter, Graeme

AU - Katritch, Vsevolod

AU - Abagyan, Ruben

AU - Cherezov, Vadim

AU - Liu, Wei

AU - Han, Gye Won

AU - Kobayashi, Takuya

AU - Stevens, Raymond C.

AU - Iwata, So

PY - 2011/7/7

Y1 - 2011/7/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79960070651&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79960070651&partnerID=8YFLogxK

U2 - 10.1038/nature10236

DO - 10.1038/nature10236

M3 - Article

C2 - 21697825

AN - SCOPUS:79960070651

VL - 475

SP - 65

EP - 72

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7354

ER -