菌根细菌的ABC载体的冷-EM结构,该载体介导了里法皮辛耐药性的介导
Yinan Wang1,2,3, Shan Gao1,2, Fangyu Wu1,2
1State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, Nankai University, Tianjin 300353, China.
概括
耐药结核病 (TB) 越来越令人担忧. 研究人员描述了Mycobacterium结核病Rv1217c-1218c转运器,揭示了其在利芬素耐药性中的作用,并为新疗法提供了结构性见解.
科学领域:
- 微生物学 微生物学
- 结构生物学 结构生物学
- 药物耐药性 药物耐药性 药物耐药性
背景情况:
- 耐药结核病 (TB) 构成了全球重大卫生挑战.
- 在Mycobacterium tuberculosis (Mtb) 中的利芬素耐药性是有效结核病治疗的主要问题.
- 在Mtb中的ATP结合盒 (ABC) 载体通过活跃的出口参与调解药物耐药性.
研究的目的:
- 为了描述Mtb Rv1217c-1218c ABC传送器的特征.
- 确定Rv1217c-1218c在不同功能状态下的冷电子显微镜结构.
- 阐明Rv1217c-1218c在利芬素耐药性中的作用的结构基础.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定高分辨率结构.
- 生物化学测定用于研究载体活性和带结合.
- 在没有和存在ATP类似物和Rifampicin的情况下对Rv1217c-1218c进行结构分析.
主要成果:
- Rv1217c-1218c 呈现出一种V型出口者的折叠.
- 在ATP模拟 (AMPPNP) 结合时观察到结构变化,影响核酸结合域 (NBD) 和跨膜域 (TMD).
- 在AMPPNP结合时,一个周等离子体门会打开,而面向周等离子体的疏水性腔就参与了里芬素的结合.
- 脂是传送器结构的组成部分.
结论:
- 该研究提供了一个结构机制,说明Rv1217c-1218c如何作为ABC出口者,在Mtb.中调解里芬辛耐药性的功能.
- 了解Rv1217c-1218c的结构和功能为开发对抗利芬素耐药性的策略提供了潜在的目标.
- 这些发现有助于深入了解菌体中药物流出的更广泛机制.
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