冷-EM揭示了多药物排放MdtB和MdtF的结构异质性和形状灵活性
Surekha Padmanaban1, Clayton Fernando Rencilin1, Rupam Biswas1,2
1Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, India.
mBio
|December 10, 2025
概括
抗性结节细胞分裂 (RND) 排泄,如大肠杆菌中的MdtB和MdtF,是多药耐药性的关键. 冷EM揭示了新的结构和动态,为抗生素流出机制提供了洞察力.
科学领域:
- 结构生物学是结构生物学.
- 微生物学 微生物学
- 生物化学 生物化学
背景情况:
- 抵抗-结节-细胞分裂 (RND) 排液对于包括*Escherichia coli*在内的格兰阴性细菌的多药性耐药性至关重要.
- 这些积极排放广泛的抗微生物药物,导致尿道感染和食物传播疾病等感染的治疗失败.
- 由于它们的重叠功能和在抗生素耐药性中的作用,了解单个RND载体的结构和机制至关重要.
研究的目的:
- 通过冷电子显微镜 (cryo-EM) 来确定从大肠杆菌 (Escherichia coli) 获得的两个不同的疏水性和两性排泄 (HAE) -RND输送体MdtB和MdtF的结构.
- 阐明这些RND载体在基质运输过程中的新型构造状态和结构动力学.
- 提供对药物结合部位和结构导向抑制剂设计对抗多药耐药细菌的运输机制的洞察力.
主要方法:
- 使用单粒子冷电子显微镜 (cryo-EM) 解析了MdtB和MdtF的结构.
- 对结构动态的分析,特别是MdtF在n-dodecyl-β-D-maltoside (DDM) 的存在下.
- 高分辨率结构确定 (2.8 Å MdtF) 检查跨膜领域的构造变化.
主要成果:
- 确定了HAE-RND排水MdtB和MdtF的新型冷电磁结构.
- MdtB结构显示了一个中间的结构状态,而MdtF表现出显著的结构动态和灵活性.
- 在其跨膜核心螺旋体和域中,MdtF显示了实质性的形状变化,突出显示了其在运输过程中的动态性质.
结论:
- 确定的结构揭示了HAE-RND排水的新型构造状态,这对于理解它们的运输机制至关重要.
- 对MdtF动态的结构洞察力为RND传送器中基板转位提供了更深入的理解.
- 这项研究奠定了开发向抑制剂的基础,通过利用这些结构机制来对抗多药耐药的大肠杆菌.
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