To achieve the full potential of pharmacogenomics, one must accurately predict the functional outcomes that arise from amino acid substitutions in proteins. Classically, researchers have focused on understanding the consequences of individual substitutions. However, literature surveys have shown that most substitutions were created at evolutionarily conserved positions. Awareness of this bias leads to a shift in perspective, from considering the outcomes of individual substitutions to understanding the roles of individual protein positions. Conserved positions tend to act as “toggle” switches, with most substitutions abolishing function. However, nonconserved positions have been found equally capable of affecting protein function. Indeed, many nonconserved positions act like functional dimmer switches (“rheostat” positions): this is revealed when multiple substitutions are made at a single position. Each substitution has a different functional outcome; the set of substitutions spans a range of outcomes. Finally, some nonconserved positions appear neutral, capable of accommodating all amino acid types without modifying function. This paper reviews the currently-known properties of rheostat positions, with examples shown for pyruvate kinase, organic anion transporting polypeptide 1B1, the beta-lactamase inhibitory protein, and angiotensin-converting enzyme 2. Outcomes observed for rheostat positions have implications for the rational design of drug analogs and allosteric drugs. Furthermore, this new framework—comprising three types of protein positions—provides a new approach to interpreting disease and population-based databases of amino acid changes. In conclusion, although a full understanding of substitution outcomes at rheostat positions poses a challenge, utilization of this new frame of reference will further advance the application of pharmacogenomics.

中文翻译：

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变阻器位置：与药物基因组学相关的蛋白质位置的新分类。


为了充分发挥药物基因组学的潜力，必须准确预测蛋白质中氨基酸取代所产生的功能结果。传统上，研究人员专注于了解个体替代的后果。然而，文献调查表明，大多数替代是在进化保守的位置上产生的。对这种偏见的认识导致了观点的转变，从考虑个体替换的结果到理解个体蛋白质位置的作用。保守位置往往充当“切换”开关，大多数替换废除了功能。然而，已发现非保守位置同样能够影响蛋白质功能。事实上，许多非保守位置的作用就像功能调光器开关（“变阻器”位置）：当在单个位置进行多个替换时，就会揭示这一点。每次替代都有不同的功能结果；这组替代涵盖了一系列结果。最后，一些非保守位置呈现中性，能够容纳所有氨基酸类型而不改变功能。本文回顾了当前已知的变阻器位置特性，并以丙酮酸激酶、有机阴离子转运多肽 1B1、β-内酰胺酶抑制蛋白和血管紧张素转换酶 2 为例。观察到的变阻器位置结果对合理设计具有重要意义药物类似物和变构药物。此外，这个新框架包含三种类型的蛋白质位置，提供了一种解释疾病和基于人群的氨基酸变化数据库的新方法。 总之，尽管充分理解变阻器位置的替代结果提出了挑战，但利用这种新的参考框架将进一步推进药物基因组学的应用。