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首页> 外文期刊>Chemistry: A European journal >From lin-benzoguanines to lin-benzohypoxanthines as ligands for zymomonas mobilis tRNA-guanine transglycosylase: Replacement of protein-ligand hydrogen bonding by importing water clusters
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From lin-benzoguanines to lin-benzohypoxanthines as ligands for zymomonas mobilis tRNA-guanine transglycosylase: Replacement of protein-ligand hydrogen bonding by importing water clusters

机译：从林-苯鸟嘌呤到林-苯并黄嘌呤作为运动发酵单胞菌的配体tRNA-鸟嘌呤转糖基化酶：通过引入水簇来取代蛋白质-配体氢键

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The foodborne illness shigellosis is caused by Shigella bacteria that secrete the highly cytotoxic Shiga toxin, which is also formed by the closely related enterohemorrhagic Escherichia coli (EHEC). It has been shown that tRNA-guanine transglycosylase (TGT) is essential for the pathogenicity of Shigella flexneri. Herein, the molecular recognition properties of a guanine binding pocket in Zymomonas mobilis TGT are investigated with a series of lin-benzohypoxanthine- and lin-benzoguanine-based inhibitors that bear substituents to occupy either the ribose-33 or the ribose-34 pocket. The three inhibitor scaffolds differ by the substituent at C(6) being H, NH _2, or NH-alkyl. These differences lead to major changes in the inhibition constants, pK _a values, and binding modes. Compared to the lin-benzoguanines, with an exocyclic NH _2 at C(6), the lin-benzohypoxanthines without an exocyclic NH _2 group have a weaker affinity as several ionic protein-ligand hydrogen bonds are lost. X-ray cocrystal structure analysis reveals that a new water cluster is imported into the space vacated by the lacking NH _2 group and by a conformational shift of the side chain of catalytic Asp102. In the presence of an N-alkyl group at C(6) in lin-benzoguanine ligands, this water cluster is largely maintained but replacement of one of the water molecules in the cluster leads to a substantial loss in binding affinity. This study provides new insight into the role of water clusters at enzyme active sites and their challenging substitution by ligand parts, a topic of general interest in contemporary structure-based drug design. Water replacements: A series of lin-benzopurines was evaluated as inhibitors of Zymomonas mobilis tRNA-guanine transglycosylase, an enzyme that was identified as a potential target for the treatment of shigellosis. X-ray cocrystal structures show the import of a new water cluster that replaces lost protein-ligand interactions (see figure), with an overall reduction in binding affinity.
机译：食源性志贺菌病是由分泌高度细胞毒性志贺毒素的志贺氏菌引起的，志贺菌毒素也由密切相关的肠出血性大肠杆菌（EHEC）形成。已经表明，tRNA-鸟嘌呤转糖基酶（TGT）对于弗氏志贺氏菌的致病性至关重要。在本文中，运动发酵单胞菌TGT中鸟嘌呤结合口袋的分子识别特性是用一系列带有取代基占据核糖33或核糖34口袋的基于林-苯并次黄嘌呤和林-苯并鸟嘌呤的抑制剂研究的。这三种抑制剂支架的区别在于C（6）处的取代基为H，NH _2或NH-烷基。这些差异导致抑制常数，pK _a值和结合模式发生重大变化。与在C（6）上有环外NH _2的lin-苯并鸟嘌呤相比，没有环外NH _2基团的lin-苯并次黄嘌呤具有较弱的亲和力，因为失去了几个离子蛋白-配体氢键。 X射线共晶结构分析表明，由于缺少NH _2基团和催化Asp102侧链的构象位移，新的水团被导入空出的空间。在L-苯并鸟嘌呤配体的C（6）处存在N-烷基的情况下，该水簇在很大程度上得以维持，但簇中水分子之一的置换导致结合亲和力的大幅降低。这项研究提供了对水簇在酶活性位点上的作用及其被配体部分取代的挑战性的新见解，这是当代基于结构的药物设计中普遍关注的话题。水替代品：评估了一系列的Lin-benzopurines作为运动发酵单胞菌tRNA-鸟嘌呤转糖基酶的抑制剂，该酶被确定为治疗志贺氏菌病的潜在靶标。 X射线共晶结构显示了新的水簇的导入，该簇取代了丢失的蛋白质-配体相互作用（见图），结合亲和力总体降低了。

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