Identification of the Ah-receptor structural determinants for ligand preferences.
Identification of the Ah-receptor structural determinants for ligand preferences.
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DOI：
10.1093/toxsci/kfs194
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发表时间：
2012-09
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通讯作者：
Y. Xing;M. Nukaya;K. Satyshur;Li Jiang;V. Stanevich;E. N. Korkmaz;L. Burdette;G. Kennedy;Q. Cui;C. Bradfield
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文献类型：
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作者：
Y. Xing;M. Nukaya;K. Satyshur;Li Jiang;V. Stanevich;E. N. Korkmaz;L. Burdette;G. Kennedy;Q. Cui;C. Bradfield
芳香烃受体（AHR）是一种转录因子，对不同的配体有反应，在毒理学、免疫功能和心血管生理学中起着关键作用。AHR的配体混杂和偏好的结构基础对于理解AHR功能至关重要。基于一个密切相关的蛋白质HIF 2 α的结构，我们模拟了与2，3，7，8-四氯二苯并-p-二恶英（TCDD）和苯并（a）芘（BaP）结合的AHR配体结合结构域（LBD），并通过形状和氢键势确定了控制配体偏好的残基。这些残基的突变，特别是Q377和G298，导致TCDD和BaP效力的强烈和相反的变化，以及TCDD/BaP效力比率的高达20倍的变化。该模型还揭示了一个灵活的“带”结构;分子动力学（MD）模拟表明，“带”和AHR-LBD中的其他几个结构元件比HIF 2 α更灵活，可能有助于配体混杂。TCDD同源物与人类AHR-LBD模型的分子对接将其结合亲和力排列为与其毒性的实验排名相似。我们的研究揭示了预测毒性和理解通过不同配体的AHR信号传导的关键结构基础。
The aryl hydrocarbon receptor (AHR) is a transcription factor that responds to diverse ligands and plays a critical role in toxicology, immune function, and cardiovascular physiology. The structural basis of the AHR for ligand promiscuity and preferences is critical for understanding AHR function. Based on the structure of a closely related protein HIF2α, we modeled the AHR ligand binding domain (LBD) bound to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo(a)pyrene (BaP) and identified residues that control ligand preferences by shape and H-bond potential. Mutations to these residues, particularly Q377 and G298, resulted in robust and opposite changes in the potency of TCDD and BaP and up to a 20-fold change in the ratio of TCDD/BaP efficacy. The model also revealed a flexible "belt" structure; molecular dynamic (MD) simulation suggested that the "belt" and several other structural elements in the AHR-LBD are more flexible than HIF2α and likely contribute to ligand promiscuity. Molecular docking of TCDD congeners to a model of human AHR-LBD ranks their binding affinity similar to experimental ranking of their toxicity. Our study reveals key structural basis for prediction of toxicity and understanding the AHR signaling through diverse ligands.