Department of Chemistry, University of Alabama in Huntsville, 301 Sparkman Drive, Huntsville, AL 35899, USA.
Int J Mol Sci. 2013 Nov 19;14(11):22741-52. doi: 10.3390/ijms141122741.
Bacterial Pth1 is essential for viability. Pth1 cleaves the ester bond between the peptide and nucleotide of peptidyl-tRNA generated from aborted translation, expression of mini-genes, and short ORFs. We have determined the shape of the Pth1:peptidyl-tRNA complex using small angle neutron scattering. Binding of piperonylpiperazine, a small molecule constituent of a combinatorial synthetic library common to most compounds with inhibitory activity, was mapped to Pth1 via NMR spectroscopy. We also report computational docking results, modeling piperonylpiperazine binding based on chemical shift perturbation mapping. Overall these studies promote Pth1 as a novel antibiotic target, contribute to understanding how Pth1 interacts with its substrate, advance the current model for cleavage, and demonstrate feasibility of small molecule inhibition.
细菌 Pth1 对于生存是必需的。Pth1 切割从翻译中止、小基因表达和短 ORF 产生的肽基-tRNA 中的肽和核苷酸之间的酯键。我们使用小角度中子散射确定了 Pth1：肽基-tRNA 复合物的形状。通过 NMR 光谱学将胡椒基哌嗪（组合合成文库中小分子成分，该文库是大多数具有抑制活性化合物的共同组成部分）结合到 Pth1 上进行了映射。我们还报告了计算对接结果，基于化学位移扰动映射模拟胡椒基哌嗪结合。总的来说，这些研究促进了 Pth1 作为一种新型抗生素靶标，有助于理解 Pth1 如何与其底物相互作用，推进当前的切割模型，并证明了小分子抑制的可行性。
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