由单个突变引起的形状变化驱动的新德里金属β-乳糖酶的抑制剂依赖性耐受性
Liwen Huang1,2,3,4, Tsz-Fung Wong1,2, Qipeng Cheng2,5
1Department of Applied Biology and Chemical Technology, Food Safety and Technology Research Centre, and Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Kowloon 999077, Hong Kong SAR, China.
Journal of the American Chemical Society
|July 21, 2025
概括
新德里金属β-乳糖酶 (NDM) 变种通过构造变化进化,M154L突变通过调节蛋白质动态来增强耐药性. 这揭示了设计NDM抑制剂的新策略.
科学领域:
- 生物化学
- 结构生物学
- 抗菌药物耐药性
背景情况:
- 甲基β-乳糖酶 (MBL),特别是新德里甲基β-乳糖酶 (NDM),在抗菌耐药性危机中具有关键作用,因为它们能够化β-乳糖抗生素.
- 了解NDM变体的进化机制和构造动态对于开发有效的抑制剂至关重要.
研究的目的:
- 通过/交换质谱法 (HDX-MS) 调查NDM变体的结构动态及其对抑制剂的反应.
- 阐明α3-L8-β8区域和M154L突变在NDM耐药性演变和抑制剂相互作用中的作用.
主要方法:
- 采用/交换质谱法 (HDX-MS) 来绘制NDM的构造格局.
- 在无体和受抑制剂结合状态下分析NDM (l-captopril,d-captopril,ebselen,aspergillomarasmine A).
- 研究M154L突变对NDM形状灵活性和动态的影响.
主要成果:
- 在抑制剂结合时,在α3-L8-β8区域中发现了保留的异质指纹,表明其在异质调节中的作用.
- 证明M154L突变显著改变形状灵活性并放大抑制剂特异性反应.
- 在限制条件下观察到α3-L8区域和活性位点循环区域的改变HDX模式,这表明突变驱动的适应.
结论:
- 该α3-L8区域被确定为NDM的形状适应性至关重要的神秘异构位点.
- 这种M154L突变作为一个全调节器, 重新连接远程动态通信并增强耐药性.
- 针对α3-L8区域的构成导向抑制剂设计是对抗NDM介导的抗菌耐药性的有希望的策略.
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