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独特和常见的激动剂激活昆虫幼年激素受体和人类AHR
David Sedlak1, Roman Tuma2, Jayaprakash Narayana Kolla3
1Institute of Molecular Genetics, Czech Academy of Sciences, Prague 14220, Czech Republic.
作为杀虫剂使用的合成昆虫青春激素激素激剂可能会干扰人类酸碳化合物受体 (AHR) 途径. 这项研究确定了新型激动剂,并揭示了对受体激活的结构性见解.
科学领域:
- 内分泌学 在内分泌学.
- 分子生物学分子生物学
- 毒理学 毒理学 毒理学
背景情况:
- bHLH-PAS家族包括关键受体,如脊椎动物中的酸受体 (AHR) 和昆虫中的青春激素受体 (JHR).
- AHR和JHR都结合小分子来调节生理过程,其中JHR是杀虫剂的目标,而AHR参与了人类内分泌平衡和对污染物的反应.
研究的目的:
- 调查激活昆虫JHR信号的化合物是否也可以影响人类AHR信号.
- 确定新型JHR激动剂,并探索JHR和AHR中连接体结合和受体激活的结构基础.
主要方法:
- 使用Drosophila基于细胞的记者系统选5万个化合物库,以识别JHR激动剂.
- 测试在人类细胞系记者试验中确定了JHR激动因子,以评估AHR信号调制.
- 利用分子动力学建模和局部定向突变发生来比较AHR和JHR的联结腔和相互作用.
主要成果:
- 确定了93种新的JHR激动剂,其中26%也调节人类的AHR信号,这表明它们的激动剂谱系有显著的重叠.
- 分子建模揭示了AHR和JHR的结合腔中的连接体特异性和保存特征.
- 突变性研究证实了预测的配体受体相互作用的意义.
结论:
- 针对昆虫的合成青春激素激动剂 (JHR) 可能作为人类AHR通路的内分泌干扰剂.
- 结合体结合口袋的结构相似性和差异解释了JHR和AHR激动剂之间的交叉反应.
- 这些发现突出了暴露于杀虫剂对人类内分泌健康的潜在风险.
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