An evolution-based strategy for engineering allosteric regulation.
An evolution-based strategy for engineering allosteric regulation.
复制标题
一种基于进化的工程变构调节策略。
DOI：
10.1088/1478-3975/aa64a4
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发表时间：
2017
期刊：
影响因子：
2
通讯作者：
Reynolds,KimberlyA
中科院分区：
文献类型：
--
作者：
Pincus,David;Resnekov,Orna;Reynolds,KimberlyA
变构调节提供了一种在毫秒到几秒的时间尺度上控制细胞内蛋白质活性的方法。设计合成变构系统的能力将对开发新型生物传感器、创建合成细胞信号通路以及设计具有调节作用的小分子药物具有实用价值。为此，我们概述了一种通用的方法--保守热点的变构理性工程(REACH)--通过利用潜在的变构引入到感兴趣的蛋白质中，这种潜在的变构已经被进化固定到其结构中。REACH需要使用统计耦合分析(SCA)来识别蛋白质表面的“变构热点”，开发和实施实验分析来测试热点的功能，以及一个变构调节器工具包来影响内源细胞电路。REACH可以广泛应用于重新连接细胞过程，以响应新的输入。
Allosteric regulation provides a way to control protein activity at the time scale of milliseconds to seconds inside the cell. An ability to engineer synthetic allosteric systems would be of practical utility for the development of novel biosensors, creation of synthetic cell signaling pathways, and design of small molecule pharmaceuticals with regulatory impact. To this end, we outline a general approach—termed rational engineering of allostery at conserved hotspots (REACH)—to introduce novel regulation into a protein of interest by exploiting latent allostery that has been hard-wired by evolution into its structure. REACH entails the use of statistical coupling analysis (SCA) to identify'allosteric hotspots' on protein surfaces, the development and implementation of experimental assays to test hotspots for functionality, and a toolkit of allosteric modulators to impinge on endogenous cellular circuitry. REACH can be broadly applied to rewire cellular processes to respond to novel inputs.