PDF(Pubmed)
Abstract：
In silico approaches were employed to examine the characteristics of interactions between human mitochondrial thioredoxin 2 (HsTrx2) and its 38 previously identified mitochondrial protein ligands. All interactions appeared driven mainly by electrostatic forces. The statistically significant residues of HsTrx2 for interactions were characterized as \"contact hot spots\". Since these were identical/adjacent to putative thermodynamic hot spots, an energy network approach identified their neighbors to highlight possible contact interfaces. Three distinct areas for binding emerged: (i) one around the active site for covalent interactions, (ii) another antipodal to the active site for strong non-covalent interactions, and (iii) a third area involved in both kinds of interactions. The contact interfaces of HsTrx2 were projected as respective interfaces for Escherichia coli Trx1 (EcoTrx1), 2, and HsTrx1. Comparison of the interfaces and contact hot spots of HsTrx2 to the contact residues of EcoTx1 and HsTrx1 from existing crystal complexes with protein ligands supported the hypothesis, except for a part of the cleft/groove adjacent to Trp30 preceding the active site. The outcomes of this study raise the possibility for the rational design of selective inhibitors for the interactions of HsTrx2 with specific protein ligands without affecting the entirety of the functions of the Trx system.
摘要：
采用计算机模拟方法来检查人线粒体硫氧还蛋白2（HsTrx2）与其38个先前鉴定的线粒体蛋白配体之间的相互作用特征。所有的相互作用主要由静电力驱动。HsTrx2相互作用的统计学显著残基被表征为“接触热点”。由于这些与假定的热力学热点相同/相邻，一种能源网络方法确定了它们的邻居，以突出显示可能的联系界面。出现了三个不同的结合区域：（i）一个围绕共价相互作用的活性位点，（ii）活性位点的另一个反足性强的非共价相互作用，和(iii)涉及两种相互作用的第三领域。HsTrx2的接触界面被投影为大肠杆菌Trx1（EcoTrx1）的相应界面，2和HsTrx1。HsTrx2的界面和接触热点与来自现有晶体复合物与蛋白质配体的EcoTx1和HsTrx1的接触残基的比较支持了这一假设，除了与活性位点之前的Trp30相邻的一部分裂口/沟。这项研究的结果提高了合理设计HsTrx2与特定蛋白质配体相互作用的选择性抑制剂的可能性，而不会影响Trx系统的全部功能。
