A Closed Form Model for Molecular Ratchet-Type Chemically Induced Dimerization Modules
A Closed Form Model for Molecular Ratchet-Type Chemically Induced Dimerization Modules
复制标题
分子棘轮型化学诱导二聚模块的封闭模型
DOI：
10.1021/acs.biochem.2c00172
复制
发表时间：
2022
期刊：
影响因子：
2.9
通讯作者：
Whitehead, Timothy A.
中科院分区：
文献类型：
--
作者：
Steiner, Paul J.;Swift, Samuel D.;Bedewitz, Matthew;Wheeldon, Ian;Cutler, Sean R.;Nusinow, Dmitri A.;Whitehead, Timothy A.
化学诱导二聚化（CID）模块使用户能够实现配体控制的细胞和生化功能，以解决基础和应用生物学中的许多问题。一类特殊的CID模块天然存在于植物中，涉及结合激素的激素受体，引发受体的构象变化，从而能够被第二种结合蛋白识别。最近的两份报告表明，这种激素受体可以被改造成感知几十种结构不同的化合物。作为一个封闭的形式模型的分子棘轮将是巨大的效用在生物系统的正向工程，在这里，我们已经开发了一个封闭的形式模型，这些不同的CID模块。这些模块，我们称之为分子棘轮，是不同于更常见的CID模块称为分子胶，因为它们从事饱和结合动力学，其特征在于以及由希尔方程。分子棘轮的一个定义性特征是响应的灵敏度可以通过增加激素受体与结合蛋白的摩尔比来调节。因此，相同的分子棘轮可以具有皮科或微摩尔EC 50，这取决于不同受体和结合蛋白的浓度。推导出基础基元反应速率模型、受体和结合蛋白的非配体依赖性复合以及激素受体的同二聚化的封闭形式模型。各种ofin vitroandin vivo应用程序的有用的控制方程推导，包括酶联免疫吸附测定样微孔板测定，原核生物和真核生物中的转录激活，配体诱导的分裂蛋白互补。
Chemical-induced dimerization (CID) modules enable users to implement ligand-controlled cellular and biochemical functions for a number of problems in basic and applied biology. A special class of CID modules occur naturally in plants and involve a hormone receptor that binds a hormone, triggering a conformational change in the receptor that enables recognition by a second binding protein. Two recent reports show that such hormone receptors can be engineered to sense dozens of structurally diverse compounds. As a closed form model for molecular ratchets would be of immense utility in forward engineering of biological systems, here we have developed a closed form model for these distinct CID modules. These modules, which we call molecular ratchets, are distinct from more common CID modules called molecular glues in that they engage in saturable binding kinetics and are characterized well by a Hill equation. A defining characteristic of molecular ratchets is that the sensitivity of the response can be tuned by increasing the molar ratio of the hormone receptor to the binding protein. Thus, the same molecular ratchet can have a pico- or micromolar EC50depending on the concentration of the different receptor and binding proteins. Closed form models are derived for a base elementary reaction rate model, for ligand-independent complexation of the receptor and binding protein, and for homodimerization of the hormone receptor. Useful governing equations for a variety ofin vitroandin vivoapplications are derived, including enzyme-linked immunosorbent assay-like microplate assays, transcriptional activation in prokaryotes and eukaryotes, and ligand-induced split protein complementation.