Chemical Scale Studies of the Phe-Pro Conserved Motif in the Cys Loop of Cys Loop Receptors
Chemical Scale Studies of the Phe-Pro Conserved Motif in the Cys Loop of Cys Loop Receptors
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DOI：
10.1074/jbc.m109.060939
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发表时间：
2010-03-19
影响因子：
4.8
通讯作者：
Dougherty, Dennis A.
中科院分区：
文献类型：
--
作者：
Limapichat, Walrati;Lester, Henry A.;Dougherty, Dennis A.
研究了位于烟碱乙酰胆碱受体Cys环顶端的两个保守残基Phe（135）和Pro（136）的功能。这两个残基分别被天然和非天然氨基酸取代，重点研究了Phe（135）的芳香性、Pro（136）的主链构象、侧链的极性和体积以及芳香侧链与脯氨酸之间的特定相互作用。对含有脯氨酸和非天然脯氨酸类似物的模型肽的核磁共振波谱研究表明，相对于缺乏脯氨酸的肽，顺式构象的数量一致增加。在受体中，Phe和Pro残基之间的强烈相互作用是显而易见的，因为Phe位点对芳香性和疏水性有强烈的偏好。在脯氨酸位点观察到类似的疏水性影响。此外，通过一系列简单的同源脯氨酸类似物，结果揭示了受体功能与脯氨酸主链上的顺式偏倚之间的相关性。这可能表明该位点的顺式脯氨酸构象在受体功能中起重要作用。
The functions of two conserved residues, Phe(135) and Pro(136), located at the apex of the Cys loop of the nicotinic acetylcholine receptor are investigated. Both residues were substituted with natural and unnatural amino acids, focusing on the role of aromaticity at Phe(135), backbone conformation at Pro(136), side chain polarity and volume, and the specific interaction between the aromatic side chain and the proline. NMR spectroscopy studies of model peptides containing proline and unnatural proline analogues following a Phe show a consistent increase in the population of the cis conformer relative to peptides lacking the Phe. In the receptor, a strong interaction between the Phe and Pro residues is evident, as is a strong preference for aromaticity and hydrophobicity at the Phe site. A similar influence of hydrophobicity is observed at the proline site. In addition, across a simple homologous series of proline analogues, the results reveal a correlation between receptor function and cis bias at the proline backbone. This could suggest a significant role for the cis proline conformer at this site in receptor function.