对ABC传递器MsbA的双模式抑制的结构基础
Hoangdung Ho1, Anh Miu2, Mary Kate Alexander3
1Structural Biology, Genentech Inc., San Francisco, CA, USA.
Nature
|May 4, 2018
概括
研究人员发现一个叫G907的小分子如何抑制MsbA, 这一发现揭示了调节ATP结合盒载体和设计新型抗生素的新机制.
科学领域:
- 结构生物学
- 微生物学
- 药理学
背景情况:
- 通过格拉姆阴性细菌的内膜传输核脂多糖是至关重要的,由ATP结合盒 (ABC) 传输器MsbA介导.
- 虽然MsbA的结构提供了对脂质运输的洞察力,但对其药理学调节的理解是有限的.
研究的目的:
- 阐明小分子抗剂G907对MsbA抑制的结构基础.
- 揭示ABC输送器对抗的新机制,
主要方法:
- 确定了与G907复合的MsbA的2.9 Å分辨率结构.
- 使用结构分析来确定G907诱导的结合部位和形状变化.
主要成果:
- G907通过结合到保存的跨膜口袋,将MsbA捕获到面向内部的,与脂多糖结合的形状中.
- 通过解离核酸结合域,G907诱导了第二种全抑制机制.
结论:
- 这项研究揭示了G907对ABC输送体的前所未有的抑制机制.
- 提供了选择性调节ABC载体和针对MsbA的新抗生素的合理设计的框架.
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