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芳香烃受体(Aryl hydrocarbon receptor,AhR)属于配体依赖性的转录因子蛋白。本文通过对AhR配体结合区域(Ligand binding domain,LBD)的结构功能及物种特异性分析,发现在其结合腔口有一些关键残基可能起到“门控”作用,进一步将野生型(WT)和3个突变模型(Phe289Ala、Tyr316Ala、Ile319Ala)进行分子动力学模拟,从蛋白稳定性、蛋白结构变化、蛋白结合腔变化及蛋白和配体结合能力4个方面分析3个残基的门控作用。研究发现,Phe289、Tyr316、Ile319氨基酸残基通过形成疏水作用为AhR LBD起到“门控”作用;而将这些氨基酸分别突变后,其蛋白稳定性降低,整体运动性增加,配体亲和力减弱,其中Tyr316、Ile319对腔内体积影响较大,Phe289使腔内环境稳定性降低。本研究可为基于芳香烃受体的药物设计提供相关理论指导。
Aryl hydrocarbon receptor (AhR) belongs to a ligand-dependent transcription factor protein. Based on the structural and species-specific analysis of AhR Ligand binding domain (LBD), we found that there are some key residues in the binding site of AhR that may play a role in “gating” (WT) and three mutant models (Phe289Ala, Tyr316Ala and Ile319Ala) were used to perform molecular dynamics simulations. The three residues (3 residues) were analyzed in terms of protein stability, protein structure changes, protein binding cavity changes and protein and ligand binding ability Gating effect. It was found that the amino acid residues of Phe289, Tyr316 and Ile319 play a role of “gating ” by forming a hydrophobic interaction with AhR LBD. However, when these amino acids were mutated separately, their protein stability decreased, their global motility increased and their ligand affinity Weakened. Among them, Tyr316 and Ile319 had a great influence on intraluminal volume, and Phe289 decreased intracavitary stability. This study can provide theoretical guidance for the design of aromatic hydrocarbon receptor-based drugs.