López Abraham, Herranz-Trillo Fátima, Kotev Martin, Gairí Margarida, Guallar Víctor, Bernadó Pau, Millet Oscar, Tarragó Teresa, Giralt Ernest
Chemistry and Molecular Pharmacology Program, Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.
Department of Organic Chemistry, University of Barcelona, Martí i Franquès, 1-11, 08028, Barcelona, Spain.
Chembiochem. 2016 May 17;17(10):913-7. doi: 10.1002/cbic.201600102. Epub 2016 Mar 30.
Deciphering conformational dynamics is crucial for understanding the biological functions of proteins and for designing compounds targeting them. In particular, providing an accurate description of microsecond-millisecond motions opens the opportunity for regulating protein-protein interactions (PPIs) by modulating the dynamics of one interacting partner. Here we analyzed the conformational dynamics of prolyl oligopeptidase (POP) and the effects of active-site-directed inhibitors on the dynamics. We used an integrated structural biology approach based on NMR spectroscopy and SAXS experiments complemented by MD simulations. We found that POP is in a slow equilibrium in solution between open and closed conformations, and that inhibitors effectively abolished this equilibrium by stabilizing the enzyme in the closed conformation.
解析构象动力学对于理解蛋白质的生物学功能以及设计针对它们的化合物至关重要。特别是，准确描述微秒至毫秒级的运动为通过调节一个相互作用伙伴的动力学来调控蛋白质-蛋白质相互作用（PPI）提供了机会。在这里，我们分析了脯氨酰寡肽酶（POP）的构象动力学以及活性位点导向抑制剂对动力学的影响。我们使用了一种基于核磁共振光谱和小角X射线散射实验并辅以分子动力学模拟的综合结构生物学方法。我们发现，POP在溶液中处于开放和闭合构象之间的缓慢平衡状态，并且抑制剂通过将酶稳定在闭合构象中有效地消除了这种平衡。
