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タイトル: | Structure of the human histamine H1 receptor complex with doxepin. |
著者: | 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 ![]() ![]() |
著者名の別形: | 小林, 拓也 |
キーワード: | Structural biology Drug discovery Biochemistry Medical research |
発行日: | 7-Jul-2011 |
出版者: | Nature Publishing Group |
誌名: | Nature |
巻: | 475 |
号: | 7354 |
開始ページ: | 65 |
終了ページ: | 70 |
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. |
著作権等: | © 2011 Nature Publishing Group, a division of Macmillan Publishers Limited. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 This is not the published version. Please cite only the published version. |
URI: | http://hdl.handle.net/2433/156845 |
DOI(出版社版): | 10.1038/nature10236 |
PubMed ID: | 21697825 |
出現コレクション: | 学術雑誌掲載論文等 |
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