2012年3月
Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine
NATURE COMMUNICATIONS
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- 巻
- 3
- 号
- 開始ページ
- 714
- 終了ページ
- 714
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1038/ncomms1703
- 出版者・発行元
- NATURE PUBLISHING GROUP
ELIC, the pentameric ligand-gated ion channel from Erwinia chrysanthemi, is a prototype for Cys-loop receptors. Here we show that acetylcholine is a competitive antagonist for ELIC. We determine the acetylcholine-ELIC cocrystal structure to a 2.9-angstrom resolution and find that acetylcholine binding to an aromatic cage at the subunit interface induces a significant contraction of loop C and other structural rearrangements in the extracellular domain. The side chain of the pore-lining residue F247 reorients and the pore size consequently enlarges, but the channel remains closed. We attribute the inability of acetylcholine to activate ELIC primarily to weak cation-pi and electrostatic interactions in the pocket, because an acetylcholine derivative with a simple quaternary-to-tertiary ammonium substitution activates the channel. This study presents a compelling case for understanding the structural underpinning of the functional relationship between agonism and competitive antagonism in the Cys-loop receptors, providing a new framework for developing novel therapeutic drugs.
- リンク情報
- ID情報
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- DOI : 10.1038/ncomms1703
- ISSN : 2041-1723
- PubMed ID : 22395605
- Web of Science ID : WOS:000302630100003