Comparison of histidine recognition in human and trypanosomatid histidyl-tRNA synthetases.
Comparison of histidine recognition in human and trypanosomatid histidyl-tRNA synthetases.
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DOI：
10.1016/j.biochi.2014.08.005
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发表时间：
2014-11
期刊：
影响因子：
3.9
通讯作者：
Hol, Wim G. J.
中科院分区：
文献类型：
--
作者：
Koh, Cho Yeow;Wetzel, Allan B.;de van der Schueren, Will J.;Hol, Wim G. J.
作为一个旨在获得针对锥虫tRNA合成酶的选择性抑制剂和类药物的项目的一部分，我们已经阐明了人胞浆组氨酸-tRNA合成酶(HS-cHisRS)的晶体结构，以便能够比较人和寄生虫酶。HS-cHisRS·His的结构代表了酶的底物结合状态(H-状态)。它提供了一个有趣的机会来与最近发表的无配体和咪唑结合结构HS-cHisRS进行比较，这两个结构都代表了酶的无配体状态(F-状态)。与F态结构相比，H态HS-cHisRS经历了活性中心残基和HisRS的几个保守基序的构象变化。组氨酸与HisRs形成八个氢键，其中六个与该氨基酸的氨基和羧基相连。已发表的咪唑结合结构的可获得性为剖析组氨酸的单个化学基团的结构作用提供了独特的机会。值得注意的是，分析揭示了氨基和羧酸基以及组氨酸在导致H-状态的这些戏剧性构象变化中的重要性。此外，与以前发表的锥虫HisRS结构的比较显示，寄生虫酶的F状态中有一个口袋，这可能为开发布氏锥虫HisRS的特定抑制剂提供机会。
As part of a project aimed at obtaining selective inhibitors and drug-like compounds targeting tRNA synthetases from trypanosomatids, we have elucidated the crystal structure of human cytosolic histidyl-tRNA synthetase (Hs-cHisRS) in complex with histidine in order to be able to compare human and parasite enzymes. The resultant structure of Hs-cHisRS·His represents the substrate-bound state (H-state) of the enzyme. It provides an interesting opportunity to compare with ligand-free and imidazole-bound structures Hs-cHisRS published recently, both of which represent the ligand-free state (F-state) of the enzyme. The H-state Hs-cHisRS undergoes conformational changes in active site residues and several conserved motif of HisRS, compared to F-state structures. The histidine forms eight hydrogen bonds with HisRS of which six engage the amino and carboxylate groups of this amino acid. The availability of published imidazole-bound structure provides a unique opportunity to dissect the structural roles of individual chemical groups of histidine. Remarkably, the analysis revealed the importance of the amino and carboxylate groups, of the histidine in leading to these dramatic conformational changes of the H-state. Further, comparison with previously published trypanosomatid HisRS structures reveals a pocket in the F-state of the parasite enzyme that may provide opportunities for developing specific inhibitors of Trypanosoma brucei HisRS.
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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发表时间：
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期刊：
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