在细菌细胞壁合成中抑制脂质I的结构见解
Ben C Chung1, Ellene H Mashalidis1, Tetsuya Tanino2
1Department of Biochemistry, Duke University Medical Center, 303 Research Drive, Durham, North Carolina, 27710, USA.
Nature
|April 19, 2016
概括
对Muraycin D2抑制的结构洞察力显示出很大的形状变化. 了解这些机制可以指导针对细菌糖生物合成的新抗生素的开发.
科学领域:
- 微生物学
- 结构生物学
- 药物发现
背景情况:
- 抗生素耐药的细菌感染对全球健康构成重大威胁.
- 糖生物合成是新型抗生素开发的验证目标.
- MraY (- MurNAc- 五转位酶) 是糖合成中的关键酶,也是有前途的抗生素标.
研究的目的:
- 通过其天然核酸抑制剂muraymycin D2阐明MraY抑制的结构基础.
- 了解MraY在抑制剂结合后的结构变化.
- 为设计针对MraY的新抗生素提供见解.
主要方法:
- 使用X射线结晶学来确定与muraymycin D2 (MD2) 复合的Aquifex aeolicus MraY (MraYAA) 的结构.
- 分析晶体结构以确定结合相互作用和构造变化.
主要成果:
- 在MD2结合时,晶体结构显示了MraYAA的大型结构重组,形成了不同的核酸结合和结合位点.
- MD2通过一种独特的机制与MraYAA结合,而不与关键的催化残留物或Mg2+) 辅因子相互作用.
- 结合MD2不同于天然基质UDP-MurNAc-pentapeptide,因为不需要酸盐和糖分来相互作用.
结论:
- MraY的形状可塑性有助于各种抑制剂的结合.
- 确定MD2与MraYAA的结合原理为设计针对MraY和WecA和TarO等相关酶的新型抗生素提供了基础.
- 这种结构信息对于推动急需的抗菌剂的开发至关重要.
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