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变构功能调节的起源:多条预先存在的途径。

The origin of allosteric functional modulation: multiple pre-existing pathways.

机构信息

Bioinformatics Research Unit, Research and Development Division, Fujirebio Inc., Hachioji-shi, Tokyo, Japan.

出版信息

Structure. 2009 Aug 12;17(8):1042-50. doi: 10.1016/j.str.2009.06.008.

Abstract

Although allostery draws increasing attention, not much is known about allosteric mechanisms. Here we argue that in all proteins, allosteric signals transmit through multiple, pre-existing pathways; which pathways dominate depend on protein topologies, specific binding events, covalent modifications, and cellular (environmental) conditions. Further, perturbation events at any site on the protein surface (or in the interior) will not create new pathways but only shift the pre-existing ensemble of pathways. Drugs binding at different sites or mutational events in disease shift the ensemble toward the same conformations; however, the relative populations of the different states will change. Consequently the observed functional, conformational, and dynamic effects will be different. This is the origin of allosteric functional modulation in dynamic proteins: allostery does not necessarily need to invoke conformational rearrangements to control protein activity and pre-existing pathways are always defaulted to during allostery regardless of the stimulant and perturbation site in the protein.

摘要

尽管变构作用越来越受到关注,但人们对变构机制知之甚少。在这里,我们认为在所有蛋白质中,变构信号通过多个预先存在的途径传递;哪些途径占主导地位取决于蛋白质拓扑结构、特定的结合事件、共价修饰和细胞(环境)条件。此外,蛋白质表面(或内部)上的任何位置的扰动事件不会创建新的途径,而只会改变预先存在的途径集合。在不同部位结合的药物或疾病中的突变事件会使途径集合向相同的构象转变;然而,不同状态的相对比例会发生变化。因此,观察到的功能、构象和动态效应将是不同的。这就是动态蛋白质中变构功能调节的起源:变构不一定需要引发构象重排来控制蛋白质活性,并且无论蛋白质中的刺激和扰动部位如何,预先存在的途径总是默认的。

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