Department of Medicinal Chemistry, Box 375610, University of Washington, Seattle, WA, 98177, USA.
Department of Medicinal Chemistry, Box 375610, University of Washington, Seattle, WA, 98177, USA.
Arch Biochem Biophys. 2021 Dec 15;714:109064. doi: 10.1016/j.abb.2021.109064. Epub 2021 Oct 26.
Ligand-dependent changes in protein conformation are foundational to biology. Historical mechanistic models for substrate-specific proteins are induced fit (IF) and conformational selection (CS), which invoke a change in protein conformation after ligand binds or before ligand binds, respectively. These mechanisms have important, but rarely discussed, functional relevance because IF vs. CS can differentially affect a protein's substrate specificity or promiscuity, and its regulatory properties. The modern view of proteins as conformational ensembles in both ligand free and bound states, together with the realization that most proteins exhibit some substrate promiscuity, demands a deeper interpretation of the historical models and provides an opportunity to improve mechanistic analyses. Here we describe alternative analytical strategies for distinguishing the historical models, including the more complex expanded versions of IF and CS. Functional implications of the different models are described. We provide an alternative perspective based on protein ensembles interacting with ligand ensembles that clarifies how a single protein can 'apparently' exploit different mechanisms for different ligands. Mechanistic information about protein ensembles can be optimized when they are probed with multiple ligands.
配体依赖性蛋白质构象变化是生物学的基础。历史上针对底物特异性蛋白质的机械模型是诱导契合（induced fit，IF）和构象选择（conformational selection，CS），分别是指配体结合后或结合前蛋白质构象的变化。这些机制具有重要但很少被讨论的功能相关性，因为 IF 与 CS 可以不同地影响蛋白质的底物特异性或混杂性及其调节特性。现代观点认为蛋白质在无配体和有配体结合状态下都是构象的集合体，再加上认识到大多数蛋白质表现出一定的底物混杂性，这就需要对历史模型进行更深入的解释，并提供改进机械分析的机会。在这里，我们描述了区分历史模型的替代分析策略，包括 IF 和 CS 的更复杂扩展版本。还描述了不同模型的功能意义。我们提供了一种基于与配体集合体相互作用的蛋白质集合体的替代观点，阐明了单个蛋白质如何“显然”利用不同的机制来结合不同的配体。当用多个配体探测蛋白质集合体时，可以优化有关蛋白质集合体的机械信息。
