必需内膜脂多糖-PbgA复合物的结构获解析
2020-08-14   阅读:418   来源:自然

美国基因泰克公司Steven T. Rutherford小组近日取得一项新成果。他们成功解析了必需内膜脂多糖(LPS)-PbgA复合物的结构。相关论文在线发表在2020年8月12日出版的《自然》杂志上。

在该研究中,研究人员探索了内膜蛋白PbgA的特征,并发现其缺失导致大肠杆菌毒力降低,这是通过降低LPS水平和外膜完整性实现的。与之前认为PbgA充当心磷脂转运蛋白的研究相比,利用结构分析和生理研究研究人员发现了沿内膜周质小叶的脂质A结合基序。合成的PbgA衍生肽在体外选择性结合LPS,并抑制多种革兰氏阴性细菌(包括多粘菌素抗性菌株)的生长。蛋白质组学、遗传学和药理学实验揭示了新模型,在该模型中,PbgA周质直接感知LPS通过调节LpxC(一种关键的细胞质生物合成酶)的稳定性来调控脂质A的生物合成。

总之,研究人员发现PbgA在LPS生物发生的调控过程中发挥意想不到但必不可少的作用,提供了选择性识别脂质的新结构基础,并为将来新型抗生素的发现提供了可能。

据悉,LPS是革兰氏阴性细菌外膜的主要组成成分,其发挥屏障功能。LPS会引起败血性休克而导致死亡,其脂质A核心是多粘菌素抗生素的靶点。尽管多粘菌素在临床上具有重要应用价值,并且出现了多药耐药菌株,但人们对调控LPS生物发生细菌因子的理解仍不完全。

附:英文原文

Title: Structure of the essential inner membrane lipopolysaccharide–PbgA complex

Author: Thomas Clairfeuille, Kerry R. Buchholz, Qingling Li, Erik Verschueren, Peter Liu, Dewakar Sangaraju, Summer Park, Cameron L. Noland, Kelly M. Storek, Nicholas N. Nickerson, Lynn Martin, Trisha Dela Vega, Anh Miu, Janina Reeder, Maria Ruiz-Gonzalez, Danielle Swem, Guanghui Han, Daniel P. DePonte, Mark S. Hunter, Cornelius Gati, Sheerin Shahidi-Latham, Min Xu, Nicholas Skelton, Benjamin D. Sellers, Elizabeth Skippington, Wendy Sandoval, Emily J. Hanan, Jian Payandeh, Steven T. Rutherford

Issue&Volume: 2020-08-12

Abstract: Lipopolysaccharide (LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible for barrier function1,2. LPS can cause death as a result of septic shock, and its lipid A core is the target of polymyxin antibiotics3,4. Despite the clinical importance of polymyxins and the emergence of multidrug resistant strains5, our understanding of the bacterial factors that regulate LPS biogenesis is incomplete. Here we characterize the inner membrane protein PbgA and report that its depletion attenuates the virulence of Escherichia coli by reducing levels of LPS and outer membrane integrity. In contrast to previous claims that PbgA functions as a cardiolipin transporter6,7,8,9, our structural analyses and physiological studies identify a lipid A-binding motif along the periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides selectively bind to LPS in vitro and inhibit the growth of diverse Gram-negative bacteria, including polymyxin-resistant strains. Proteomic, genetic and pharmacological experiments uncover a model in which direct periplasmic sensing of LPS by PbgA coordinates the biosynthesis of lipid A by regulating the stability of LpxC, a key cytoplasmic biosynthetic enzyme10,11,12. In summary, we find that PbgA has an unexpected but essential role in the regulation of LPS biogenesis, presents a new structural basis for the selective recognition of lipids, and provides opportunities for future antibiotic discovery.

DOI: 10.1038/s41586-020-2597-x

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