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首页> 外文期刊>International Journal of Biological Macromolecules: Structure, Function and Interactions >Characterization of active/binding site residues of peptidyl-tRNA hydrolase using biophysical and computational studies
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Characterization of active/binding site residues of peptidyl-tRNA hydrolase using biophysical and computational studies

机译：使用生物物理和计算研究表征肽基-TRNA水解酶的活性/结合位点残留物

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摘要

All mRNAs cannot be translated into full-length proteins due to ribosome-stalling that leads to release of peptidyl-tRNA which can be lethal for bacterial survival. The enzyme peptidyl-tRNA hydrolase (PtH) hydrolyses the ester bond between nascent peptide and tRNA of peptidyl-tRNA and rescues the cells from toxicity. PtH is an essential enzyme in bacteria and inhibiting this crucial enzyme can serve to combat bacterial diseases. But due to lack of understanding about the catalytic mechanism of PtH, its inhibitors have not been developed. In this work, we have carried out the binding studies of M. tuberculosis and E. coli PtH with the peptidyl-tRNA analogue (puromycin) using ITC, FTIR, CD experiments followed by docking and MD simulations to identify the potential active site residues that would help to design PtH inhibitors. Binding studies of puromycin with both PtH by ITC experiments demonstrate similar thermodynamic parameters and three fold difference in their KD. CD and FTIR studies detected changes in secondary structure composition of PtH in the presence of puromycin with different degree of perturbation. Though interactions with puromycin are conserved in both proteins, modelling studies revealed that water mediated interactions in M. tb-PtH resulting in higher affinity to puromycin. (c) 2020 Elsevier B.V. All rights reserved.
机译：由于核糖体停滞，所有MRNA不能被翻译成全长蛋白质，导致肽基-TRNA释放，用于细菌存活。酶肽基-TRNA水解酶（PTH）将肽肽和肽基-CRNA的TRNA之间的酯键水解，并从毒性抵消细胞。 PTH是细菌中的一种必需酶，并且抑制这种关键酶可以用于打击细菌疾病。但由于对PTH的催化机制缺乏了解，尚未开发其抑制剂。在这项工作中，我们使用ITC，FTIR，CD实验随后使用肽基-TRNA类似物（嘌呤霉素）对肽基-TRNA类似物（嘌呤霉素）进行了对肽基-TRNA类似物（嘌呤霉素）的结合研究，然后进行了对接和MD模拟以识别潜在的活性位点残留物有助于设计Pth抑制剂。嘌呤霉素与ITC实验的结合研究表明了其KD中类似的热力学参数和三倍倍差。 CD和FTIR研究检测到具有不同扰动程度的嘌呤霉素存在的二级结构组成的变化。虽然与嘌呤霉素的相互作用在两种蛋白质中保存，但建模研究表明，水介导的M.TB-PTH的相互作用导致嘌呤霉素更高的亲和力。 （c）2020 Elsevier B.v.保留所有权利。

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