Conformational selection or induced fit? A critical appraisal of the kinetic mechanism.
Conformational selection or induced fit? A critical appraisal of the kinetic mechanism.
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DOI：
10.1021/bi3006913
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发表时间：
2012-07-31
期刊：
影响因子：
2.9
通讯作者：
Di Cera E
中科院分区：
文献类型：
--
作者：
Vogt AD;Di Cera E
近五十年来，两种相互竞争的配体识别机制-构象选择和诱导拟合-主导了我们对生物大分子中配体结合的解释。当结合/解离事件与构象转变相比快速时，接近平衡的速率kobs根据其是否随配体浓度降低或增加而成为构象选择或诱导拟合的诊断[L]。然而，这种基于快速平衡近似的简单结论在一般情况下是不成立的。在这里，我们表明，构象选择与丰富的剧目的动力学特性，与kobs减少或增加与[L]取决于配体解离，koff，和构象异构化，KR的速率的相对大小。我们证明，即使是最简单的两步配体结合机制，减少与[L]的kobs是明确的证据的构象选择，但增加与[L]的kobs不是明确的证据诱导适合。与葡萄糖激酶、凝血酶及其前体凝血酶原-2结合的配体用作相关实例。我们的结论是，构象选择作为一种机制，配体结合到其目标可能是远比目前认为的更常见。
For almost five decades, two competing mechanisms of ligand recognition – conformational selection and induced-fit - have dominated our interpretation of ligand binding in biological macromolecules. When binding/dissociation events are fast compared to conformational transitions, the rate of approach to equilibrium, kobs, becomes diagnostic of conformational selection or induced-fit based on whether it decreases or increases with the ligand concentration, [L]. However, this simple conclusion based on the rapid-equilibrium approximation is not valid in general. Here we show that conformational selection is associated with a rich repertoire of kinetic properties, with kobs decreasing or increasing with [L] depending on the relative magnitude of the rate of ligand dissociation, koff, and the rate of conformational isomerization, kr. We prove that, even for the simplest two-step mechanism of ligand binding, a decrease of kobs with [L] is unequivocal evidence of conformational selection, but an increase of kobs with [L] is not unequivocal evidence of induced-fit. Ligand binding to glucokinase, thrombin and its precursor prethrombin-2 are used as relevant examples. We conclude that conformational selection as a mechanism for ligand binding to its target may be far more common than currently believed.
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