Exploring the Binding of Serotonin to the 5-HT3 Receptor by Density Functional Theory

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• 作者：Claudio Melis ; P.-L. Chau ; Kerry L. Price ; Sarah C. R. Lummis ; Carla Molteni
• 刊名：Journal of Physical Chemistry B
• 出版年：2006
• 出版时间：December 28, 2006
• 年：2006
• 卷：110
• 期：51
• 页码：26313 - 26319
• 全文大小：367K
• 年卷期：v.110,no.51(December 28, 2006)
• ISSN：1520-5207

文摘

The 5-HT₃ receptor is a typical ligand-gated ion channel of the Cys-loop superfamily, which is activated bybinding of serotonin (5-HT). Models of the binding site of this protein reveal potential interactions between5-HT and Tyr143, Tyr153, and Tyr234. Here we describe a series of ab initio calculations, based on densityfunctional theory, to assess the effects of mutating these tyrosine residues on the binding of 5-HT. A seriesof mutations to these tyrosines, previously studied experimentally, were tested, and the binding energiescompared with the available experimental data. Our results show that Tyr153 could form a hydrogen bondwith the tertiary amine of 5-HT, and that mutation in this location revealed binding energies broadly in linewith experimentally determined EC₅₀s. Tyr143 could also form a hydrogen bond, but as EC₅₀s do not relateto binding energies, it is unlikely that such a bond is formed here. Tyr234 is quite distinct in that it mayinteract with 5-HT via a mixed hydrogen bond/cation- interaction.