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Dynamics of an LPS translocon induced by substrate and an antimicrobial peptide
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2020-11-16 , DOI: 10.1038/s41589-020-00694-2
Francesco Fiorentino 1 , Joshua B Sauer 1, 2 , Xingyu Qiu 1 , Robin A Corey 2 , C Keith Cassidy 2 , Benjamin Mynors-Wallis 2 , Shahid Mehmood 1, 3 , Jani R Bolla 1 , Phillip J Stansfeld 2, 4 , Carol V Robinson 1
Affiliation  

Lipopolysaccharide (LPS) transport to the outer membrane (OM) is a crucial step in the biogenesis of microbial surface defenses. Although many features of the translocation mechanism have been elucidated, molecular details of LPS insertion via the LPS transport (Lpt) OM protein LptDE remain elusive. Here, we integrate native MS with hydrogen–deuterium exchange MS and molecular dynamics simulations to investigate the influence of substrate and peptide binding on the conformational dynamics of LptDE. Our data reveal that LPS induces opening of the LptD β-taco domain, coupled with conformational changes on β-strands adjacent to the putative lateral exit gate. Conversely, an antimicrobial peptide, thanatin, stabilizes the β-taco, thereby preventing LPS transport. Our results illustrate that LPS insertion into the OM relies on concerted opening movements of both the β-barrel and β-taco domains of LptD, and suggest a means for developing antimicrobial therapeutics targeting this essential process in Gram-negative ESKAPE pathogens.



中文翻译:

底物和抗菌肽诱导的 LPS 易位子动力学

脂多糖 (LPS) 转运到外膜 (OM) 是微生物表面防御生物发生的关键步骤。尽管已经阐明了易位机制的许多特征,但通过 LPS 转运 (Lpt) OM 蛋白 LptDE 插入 LPS 的分子细节仍然难以捉摸。在这里,我们将天然 MS 与氢-氘交换 MS 和分子动力学模拟相结合,以研究底物和肽结合对 LptDE 构象动力学的影响。我们的数据表明,LPS 诱导 LptD β-taco 结构域的打开,以及与假定的横向出口门相邻的 β-链的构象变化。相反,抗菌肽thanatin可以稳定β-taco,从而阻止LPS转运。

更新日期:2020-11-16
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