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对PFAS-β-乳球蛋白结合机制的结构洞察力 介导PFAS毒性
Shalja Verma1, Anika Singh2, Randhal S Ramirez Orozco3
1Department of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, Roorkee 247667, Uttarakhand, India.
牛奶蛋白β-乳糖球蛋白在其脂肪酸结合部位结合有毒的per-和多基基物质 (PFAS). 这种蛋白质可能会运输这些"永远的化学物质",可能会导致它们的神经毒性.
科学领域:
- 生物化学 生物化学
- 毒理学 毒理学 毒理学
- 结构生物学 结构生物学
背景情况:
- 和多基物质 (PFAS) 是持久的,有毒的环境污染物,由于强大的碳-键.
- 已知一种牛奶蛋白质β-乳糖球蛋白 (β-LG) 能够运输对生理功能至关重要的疏水性和两性分子.
- 由于蛋白质的运输作用和PFAS毒性,了解β-LG与PFAS的相互作用是非常重要的.
研究的目的:
- 研究PFAS与牛奶蛋白β-乳糖球蛋白的结合机制.
- 阐明PFAS-β-LG复合体形成的结构基础.
- 评估PFAS在β-LG内结合的稳定性和能量.
主要方法:
- 使用X射线晶体学来确定与PFOA,PFOS和PFDA复合的β-乳糖球蛋白的结构.
- 对晶体结构进行了生物信息学分析,以确定关键相互作用.
- 用分子动力学 (MD) 模拟来评估结合稳定性和计算结合能.
主要成果:
- 晶体结构揭示了PFOA,PFOS和PFDA与β-乳糖球蛋白的中央的高亲和结合,这是视网醇和脂肪酸的正规结合部位.
- 疏水性相互作用稳定了PFAS疏水性尾巴的结合,而极性相互作用涉及Lys60,Lys69和PFAS极性头组.
- MD模拟证实了高结合稳定性,PFDA表现出最强的结合能 (-25 kcal/mol),这是由于其较长的疏水链与有利的范德瓦尔斯相互作用.
结论:
- β-乳糖球蛋白在其疏水性葡萄杯中以高亲和力结合PFAS,利用与脂肪酸和视网醇运输相似的机制.
- 在PFAS复杂化后,蛋白质的结构经历了构造变化,包括一个开放的EF循环.
- 这项研究提出了β-乳糖球蛋白作为PFAS的载体的机制,可能调解其神经毒性作用.
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