From ab initio quantum mechanics to molecular neurobiology:: A cation-π binding site in the nicotinic receptor
From ab initio quantum mechanics to molecular neurobiology:: A cation-π binding site in the nicotinic receptor
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DOI：
10.1073/pnas.95.21.12088
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发表时间：
1998-10-13
影响因子：
11.1
通讯作者：
Dougherty, DA
中科院分区：
文献类型：
--
作者：
Zhong, WG;Gallivan, JP;Dougherty, DA
烟碱乙酰胆碱受体是原型配体门控离子通道。许多芳香族氨基酸已被鉴定为对激动剂结合位点有贡献，这表明阳离子-π相互作用可能参与激动剂乙酰胆碱的季铵基团的结合，在这里，我们显示了以下之间令人信服的相关性：（i）阳离子-pi结合能力的从头算量子力学预测和（ii）通过使用体内无义抑制法掺入非天然氨基酸，将一系列色氨酸衍生物掺入受体，乙酰胆碱在受体处的EC 50值。这种相关性在α亚基的芳香族残基-色氨酸-149中的一个且仅一个处观察到。这一发现表明，在结合时，乙酰胆碱的阳离子季铵基团使货车范德华力与α色氨酸-149的吲哚侧链接触，提供了迄今为止关于该受体的最精确的结构信息。与该模型一致，从位置α 149发出的栓系季铵基团产生组成型活性受体。
The nicotinic acetylcholine receptor is the prototype ligand-gated ion channel. A number of aromatic amino acids have been identified as contributing to the agonist binding site, suggesting that cation-pi interactions may be involved in binding the quaternary ammonium group of the agonist, acetylcholine, Here we show a compelling correlation between: (i) ab initio quantum mechanical predictions of cation-pi binding abilities and (ii) EC50 values for acetylcholine at the receptor for a series of tryptophan derivatives that were incorporated into the receptor by using the in vivo nonsense-suppression method for unnatural amino acid incorporation. Such a correlation is seen at one, and only one, of the aromatic residues-tryptophan-149 of the alpha subunit, This finding indicates that, on binding, the cationic, quaternary ammonium group of acetylcholine makes van der Waals contact with the indole side chain of alpha tryptophan-149, providing the most precise structural information to date on this receptor. Consistent with this model, a tethered quaternary ammonium group emanating from position alpha 149 produces a constitutively active receptor.