A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

James B. Hamburger; Amanda J. Hoertz; Amy Lee; Rachel J. Senturia; Dewey G. McCafferty; Patrick J. Loll

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A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

机译：抗生素雷莫拉宁二聚体的晶体结构说明了膜的定位和潜在的脂质II对接界面

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The glycodepsipeptide antibiotic ramoplanin A2 is in late stage clinical development for the treatment of infections from Gram-positive pathogens, especially those that are resistant to first line antibiotics such as vancomycin. Ramoplanin A2 achieves its antibacterial effects by interfering with production of the bacterial cell wall; it indirectly inhibits the transglycosylases responsible for peptidoglycan biosynthesis by sequestering their Lipid II substrate. Lipid II recognition and sequestration occur at the interface between the extracellular environment and the bacterial membrane. Therefore, we determined the structure of ramoplanin A2 in an amphipathic environment, using detergents as membrane mimet-ics, to provide the most physiologically relevant structural context for mechanistic and pharmacological studies. We report here the X-ray crystal structure of ramoplanin A2 at a resolution of 1.4 A. This structure reveals that ramoplanin A2 forms an intimate and highly amphipathic dimer and illustrates the potential means by which it interacts with bacterial target membranes. The structure also suggests a mechanism by which ramoplanin A2 recognizes its Lipid II ligand.

机译：糖脂肽抗生素雷莫普林A2处于晚期临床开发中，用于治疗革兰氏阳性病原体的感染，尤其是对一线抗生素（例如万古霉素）有抗药性的病原体。雷莫普林A2通过干扰细菌细胞壁的产生来达到抗菌作用。它通过隔离脂质II底物间接抑制负责肽聚糖生物合成的转糖基酶。脂质II的识别和隔离发生在细胞外环境和细菌膜之间的界面。因此，我们在两亲性环境中确定了雷莫拉宁A2的结构，使用去污剂作为膜模拟物，为机理和药理研究提供了最生理相关的结构背景。我们在这里报告了雷莫普林A2的X射线晶体结构，分辨率为1.4A。该结构揭示了雷莫普林A2形成了亲密且高度两亲的二聚体，并说明了它与细菌靶膜相互作用的潜在手段。该结构还暗示了雷莫拉宁A2识别其脂质II配体的机制。

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《Proceedings of the National Academy of Sciences of the United States of America》 |2009年第33期|13759-13764|共6页
作者
James B. Hamburger; Amanda J. Hoertz; Amy Lee; Rachel J. Senturia; Dewey G. McCafferty; Patrick J. Loll;
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作者单位

Department of Chemistry, Duke University, Durham, NC 27708;

Department of Chemistry, Duke University, Durham, NC 27708;

Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19129;

Department of Chemistry, Duke University, Durham, NC 27708;

Department of Chemistry, Duke University, Durham, NC 27708;

Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19129;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类
关键词
glycolipodepsipeptide; mechanism; vancomycin resistance;

机译：糖脂二肽机制;万古霉素耐药;

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A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface

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