Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29208, USA.
Department of Earth and Environmental Sciences, University of Milano-Bicocca, Milan, Italy.
Sci Rep. 2019 May 2;9(1):6810. doi: 10.1038/s41598-019-43232-4.
The toxic manifestations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant, primarily depend on its ability to activate aryl hydrocarbon receptor (AhR), which is a ligand-dependent transcription factor belonging to the superfamily of basic-helix-loop-helix DNA-binding proteins. In the present study, we aimed to identify novel protein receptor targets for TCDD using computational and in vitro validation experiments. Interestingly, results from computational methods predicted that Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) could be one of the potential targets for TCDD in both mouse and humans. Results from molecular docking studies showed that human VEGFR1 (hVEGFR1) has less affinity towards TCDD compared to the mouse VEGFR1 (mVEGFR1). In vitro validation results showed that TCDD can bind and phosphorylate hVEGFR1. Further, results from molecular dynamic simulation studies showed that hVEGFR1 interaction with TCDD is stable throughout the simulation time. Overall, the present study has identified VEGFR1 as a novel target for TCDD, which provides the basis for further elucidating the role of TCDD in angiogenesis.
2,3,7,8-四氯二苯并对二恶英（TCDD）是一种环境污染物，其毒性表现主要取决于其激活芳香烃受体（AhR）的能力，AhR 是一种配体依赖性转录因子，属于碱性螺旋-环-螺旋 DNA 结合蛋白超家族。在本研究中，我们旨在使用计算和体外验证实验来鉴定 TCDD 的新型蛋白质受体靶标。有趣的是，计算方法的结果预测血管内皮生长因子受体 1（VEGFR1）可能是 TCDD 在小鼠和人类中的潜在靶标之一。分子对接研究的结果表明，与 mVEGFR1 相比，人 VEGFR1（hVEGFR1）对 TCDD 的亲和力较低。体外验证结果表明，TCDD 可以与 hVEGFR1 结合并使其磷酸化。此外，分子动力学模拟研究的结果表明，hVEGFR1 与 TCDD 的相互作用在整个模拟时间内都是稳定的。总体而言，本研究确定 VEGFR1 是 TCDD 的一个新靶标，为进一步阐明 TCDD 在血管生成中的作用提供了基础。
