Motions of Allosteric and Orthosteric Ligand-Binding Sites in Proteins are Highly Correlated
Motions of Allosteric and Orthosteric Ligand-Binding Sites in Proteins are Highly Correlated
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DOI：
10.1021/acs.jcim.6b00039
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发表时间：
2016-09-01
影响因子：
5.6
通讯作者：
Lai, Luhua
中科院分区：
文献类型：
--
作者：
Ma, Xiaomin;Meng, Hu;Lai, Luhua
异构现象是其中在一个位点结合的配体影响同一大分子中的其他位点的现象。变构作用在许多生物学过程中起着重要的作用，理论上，所有的非纤维蛋白质都具有潜在的变构作用。然而，很少有变构蛋白已被验证，新的变构位点的鉴定仍然是一个挑战。残基和亚基的运动是蛋白质功能的基础，因此，我们假设变构和正构位点的运动是相关的。我们利用23个单体蛋白质的24个已知变构位点的数据集，使用高斯网络模型（GNM）计算潜在的配体结合位点和相应的正构位点之间的相关性。大多数已知的变构位点运动与相应的正构位点运动表现出高度的相关性，而其他表面空腔则没有。当使用相同蛋白质的不同结构数据时，这些高相关性是稳健的，例如载脂蛋白状态和正构效应物结合状态的结构，而不同频率模式对运动相关性的贡献取决于给定的蛋白质。在寡聚变构蛋白中也观察到变构和正构位点运动之间的高度相关性。我们应用运动相关分析来预测23个单体蛋白质中潜在的变构位点，其中一些预测与已发表的实验数据吻合良好。我们还进行了运动相关性分析，以确定一个新的变构网站15-脂氧合酶（酶在花生四烯酸代谢网络）使用最近报道的激活化合物。我们的分析正确地识别了这个新的变构位点以及目前正在实验研究的另外两个位点，沿着。我们的研究表明，变构位点的运动与正构位点的运动高度相关。我们的相关分析方法提供了新的工具，预测潜在的变构位点。
Allostery is the phenomenon in which a ligand binding at one site affects other sites in the same macromolecule. Allostery has important roles in many biological processes; Theoretically, all nonfibrous proteins are potentially allosteric. However, few allosteric proteins have been validated, and the identification of novel allosteric sites remains a challenge. The motion of residues and subunits underlies protein function; therefore, we hypothesized that the motions of allosteric and orthosteric sites are correlated. We utilized a data set of 24 known allosteric sites from 23 monomer proteins to calculate the correlations between potential ligand-binding sites and corresponding orthosteric sites using a Gaussian network model (GNM). Most of the known allosteric site motions showed high correlations with corresponding orthosteric site motions, whereas other surface cavities did not. These high correlations were robust when using different structural data for the same protein, such as structures for the apo state and the orthosteric effector-binding state, whereas the contributions of different frequency modes to motion correlations depend on the given protein. The high correlations between allosteric and orthosteric site motions were also observed in oligomeric allosteric proteins. We applied motion correlation analysis to predict potential allosteric sites in the 23 monomer proteins, and some of these predictions were in good agreement with published experimental data. We also performed motion correlation analysis to identify a novel allosteric site in 15-lipoxygenase (an enzyme in the arachidonic acid metabolic network) using recently reported activating compounds. Our analysis correctly identified this novel allosteric site along with two other sites that are currently under experimental investigation. Our study demonstrates that the motions of allosteric sites are highly correlated with the motions of orthosteric sites. Our correlation analysis method provides new tools for predicting potential allosteric sites.