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米可拉顿A与B:多尺度模拟揭示了定位和关联在异构体特定毒性的作用

John D M Nguyen¹, Gabriel C A da Hora¹, Jessica M J Swanson¹

¹Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.

|August 25, 2023

概括

布鲁利的毒素Mycolactone B比Mycolactone A更有细胞毒性,它是导致布鲁利的毒素. 这种差异源于mycolactone Bs对ER膜和Sec61转位子的更强的结合,阻断了蛋白质的产生.

科学领域:

生物化学生物化学
分子生物学分子生物学
结构生物学结构生物学

背景情况:

来自Mycobacterium ulcerans的外毒素Mycolactone,通过抑制内细胞网膜 (ER) 中的Sec61转位子引起Buruli.
存在两个主要的mycolactone异型,但只有一个表现出显著的细胞毒性.
了解这种差异性细胞毒性的结构基础对于开发向疗法至关重要.

研究的目的:

为了研究分子机制背后的微分细胞毒性mycolactone异型.
为了阐明mycolactone A和B与ER膜和Sec61转位子的特定相互作用.

主要方法:

广泛的分子动力学 (MD) 模拟与增强的自由能量采样.
利用Sec61转位子的两个不同的冷电子显微镜 (cryo-EM) 模型.
分析了与ER膜和Sec61转位子的毒素相关性.

主要成果:

与mycolactone A相比,mycolactone B与ER膜的关联性更强,可能会增加其与Sec61转位子的接近.
在不同的模型中,mycolactone B与Sec61转位子形成明显的相互作用,包括与信号识别的关键残留物以及转位子的光和侧门的更密切接触.
这些相互作用诱导了封闭的转位子构造,抑制了蛋白质转位.

结论:

增强的 mycolactone B 细胞毒性归因于其在 ER 膜的局部化增加,以及其与 Sec61 转位子诱导通道锁定关联的能力.
这些发现提供了对Buruli病变的洞察力,并建议用于诊断和基于Sec61-translocon的治疗的潜在治疗点.

关键词:

布鲁鲁利的.在 ER 膜中,有 ER 膜.第61节转换位置异构体特异性的异构体特异性通过膜透.分子动力学分子动力学这种药物是mycolactone.

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