Optimizing synthetic biological systems, for example novel metabolic pathways, becomes more complicated with more protein components. One method of taming the complexity and allowing more rapid optimization is engineering external control into components. Pharmacology is essentially the science of controlling proteins using (mainly) small molecules, and a great deal of information, spread between different databases, is known about structural interactions between these ligands and their target proteins. In principle, protein engineers can use an inverse pharmacological approach to include drug response in their design, by identifying ligand‐binding domains from natural proteins that are amenable to being included in a designed protein. In this context, “amenable” means that the ligand‐binding domain is in a relatively self‐contained subsequence of the parent protein, structurally independent of the rest of the molecule so that its function should be retained in another context. The SynPharm database is a tool, built on to the Guide to Pharmacology database and connected to various structural databases, to help protein engineers identify ligand‐binding domains suitable for transfer. This article describes the tool, and illustrates its use in seeking candidate domains for transfer. It also briefly describes already‐published proof‐of‐concept studies in which the CRISPR effectors Cas9 and Cpf1 were placed separately under the control of tamoxifen and mefipristone, by including ligand‐binding domains of the Estrogen Receptor and Progesterone Receptor in modified versions of Cas9 and Cpf1. The advantages of drug control or the rival protein‐control technology of optogenetics, for different purposes and in different situations, are also briefly discussed.

中文翻译：

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SynPharm和药理数据库指南：用于对工程蛋白进行药物控制的工具集

优化合成生物系统（例如新颖的代谢途径）变得更加复杂，同时蛋白质成分也会更多。驯服复杂性并允许更快速优化的一种方法是将外部控制设计到组件中。药理学本质上是使用（主要是）小分子控制蛋白质的科学，并且已知许多信息分布在不同的数据库之间，这些信息涉及这些配体与其靶蛋白之间的结构相互作用。原则上，蛋白质工程师可以使用逆药理学方法在设计中纳入药物反应，方法是从天然蛋白质中识别出适合设计蛋白质的配体结合域。在这种情况下，“合适的”是指配体结合结构域位于亲本蛋白的一个相对独立的子序列中，在结构上与分子的其余部分无关，因此其功能应保留在另一种情况下。SynPharm数据库是基于P指南构建的工具药物学数据库并连接到各种结构数据库，以帮助蛋白质工程师识别适合转移的配体结合域。本文介绍了该工具，并说明了该工具在寻找要转移的候选域中的用途。它还简要介绍了已发表的概念验证研究，其中通过将雌激素受体和孕激素受体的配体结合结构域包括在Cas9的改良版中，将CRISPR效应器Cas9和Cpf1分别置于他莫昔芬和米非司酮的控制下和Cpf1。还简要讨论了药物控制或光遗传学的竞争性蛋白质控制技术在不同目的和不同情况下的优势。