亲环素A -环孢菌素A复合物I折叠核心的表征：氢交换数据和刚性分析
Characterizing the folding core of the cyclophilin A - cyclosporin A complex I: hydrogen exchange data and rigidity analysis
摘要：
“折叠核心”的确定可以帮助深入了解蛋白质的结构，灵活性，流动性和动力学，从而最终了解蛋白质的功能-结构生物学的核心问题。配体结合后折叠核心的变化特别令人感兴趣，因为它们可能与药物诱导的功能变化有关。亲环素A是一种多功能的配体结合蛋白，是重要的药物靶点。它主要在蛋白质折叠过程中作为一种酶发挥作用，但也作为免疫抑制药物环孢菌素A（CsA）的主要结合伴侣。在这里，我们使用氢-氘交换（HDX）NMR光谱来确定CypA-CsA复合物的折叠核心。我们还使用了快速计算工具的刚度分析，在第一，以确定一个理论上的折叠核心的复杂。此外，我们产生了一个理论上的折叠核心的未结合的蛋白质，并比较这与以前发表的HDX数据。FIRST方法给出了一个很好的预测HDX折叠核心，但我们发现，它还没有足够的灵敏度来预测配体结合CypA的影响。
英文摘要：
The determination of a 'folding core' can help to provide insight into the structure, flexibility, mobility and dynamics, and hence, ultimately, function of a protein - a central concern of structural biology. Changes in the folding core upon ligand binding are of particular interest because they may be relevant to drug-induced functional changes. Cyclophilin A is a multi-functional ligand-binding protein and a significant drug target. It acts principally as an enzyme during protein folding, but also as the primary binding partner for the immunosuppressant drug cyclosporin A (CsA). Here, we have used hydrogen-deuterium exchange (HDX) NMR spectroscopy to determine the folding core of the CypA-CsA complex. We also use the rapid computational tool of rigidity analysis, implemented in FIRST, to determine a theoretical folding core of the complex. In addition we generate a theoretical folding core for the unbound protein and compare this with previously published HDX data. The FIRST method gives a good prediction of the HDX folding core, but we find that it is not yet sufficiently sensitive to predict the effects of ligand binding on CypA.
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