Genetic Code Expansion for Mechanistic Studies in Ion Channels: An (Un)natural Union of Chemistry and Biology,Chemical Reviews

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Genetic Code Expansion for Mechanistic Studies in Ion Channels: An (Un)natural Union of Chemistry and Biology
Chemical Reviews ( IF 51.4 ) Pub Date : 2024-08-29 , DOI: 10.1021/acs.chemrev.4c00306
Daniel T Infield ₁ , Miranda E Schene ₁ , Jason D Galpin ₁ , Christopher A Ahern ₁

Affiliation

Ion channels play central roles in biology and human health by catalyzing the transmembrane flow of electrical charge. These proteins are ideal targets for genetic code expansion (GCE) methods because it is feasible to measure ion channel activity from miniscule amounts of protein and to analyze the resulting data via rigorous, established biophysical methods. In an ideal scenario, the encoding of synthetic, noncanonical amino acids via GCE allows the experimenter to ask questions inaccessible to traditional methods. For this reason, GCE has been successfully applied to a variety of ligand- and voltage-gated channels wherein extensive structural, functional, and pharmacological data exist. Here, we provide a comprehensive summary of GCE as applied to ion channels. We begin with an overview of the methods used to encode noncanonical amino acids in channels and then describe mechanistic studies wherein GCE was used for photochemistry (cross-linking; caged amino acids) and atomic mutagenesis (isosteric manipulation of charge and aromaticity; backbone mutation). Lastly, we cover recent advances in the encoding of fluorescent amino acids for the real-time study of protein conformational dynamics.

中文翻译：

离子通道机理研究的遗传密码扩展：化学和生物学的（非）自然结合

离子通道通过催化电荷的跨膜流动，在生物学和人类健康中发挥着核心作用。这些蛋白质是遗传密码扩增（GCE）方法的理想靶标，因为可以从极少量的蛋白质中测量离子通道活性，并通过严格、成熟的生物物理方法分析所得数据。在理想情况下，通过 GCE 编码合成的非经典氨基酸允许实验者提出传统方法无法解决的问题。因此，GCE 已成功应用于各种配体和电压门控通道，其中存在广泛的结构、功能和药理学数据。在这里，我们提供了应用于离子通道的 GCE 的全面总结。我们首先概述了用于在通道中编码非经典氨基酸的方法，然后描述了 GCE 用于光化学（交联;笼状氨基酸）和原子诱变（电荷和芳香性的等位操纵;骨架突变）的机制研究。最后，我们介绍了荧光氨基酸编码的最新进展，用于蛋白质构象动力学的实时研究。

更新日期：2024-08-29

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