| 康文渊,徐锡明,郭建秀,田菲菲.化学通报,2017,80(2):179-184,207. |
| 分子动力学模拟残基突变对芳香烃受体配体结合区的影响 |
| Molecular Dynamics Studies on the Structure of Aryl hydrocarbon receptor Fragment Affected by Site-Directed Mutagenesis |
| 投稿时间：2016-07-04 修订日期：2016-08-18 |
| DOI： |
| 中文关键词: 分子模拟 分子动力学 突变 芳香烃受体 |
| 英文关键词:Molecular Simulation, Molecular Dynamics, Mutation, Aryl hydrocarbon receptor |
| 基金项目:国家自然科学基金项目（31601066、11671329);中央高校基本科研业务费专项资金（2682015CX051）;西南交通大学青年教师百人计划（2682013BR022） |
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| 中文摘要: |
| 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)和三个突变模型(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四个方面分析三个残基的门控作用。研究发现Phe289,Tyr316,Ile319三个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。研究可为基于芳香烃受体的药物设计提供相关理论指导。 |
| 英文摘要: |
| The Aryl hydrocarbon Receptor (AhR) , a ligand-actived nuclear transcription factor , regulate the expressions of a diverse group of genes when small molecules go into the pocket of its single ligand binding domain. In this study, we found Phe289, Tyr316 and Ile319 play “gatekeeper” roles via comparing Genus-species specific and structure analysis. The four mutation models (WT, Phe289Ala, Tyr316Ala, Ile319Ala) were performed using the amber99sb force field of GROMACS software package. The complex stability, protein conformational change, active site volume and binding free energy of the binary complex were analysized by “gatekeeper” residues function. The results indicated that mutagenesis will reduce the stablility of AhR ligand binding ligand(LBD) environment, and Phe289, Tyr316 and Ile319 play “gatekeeper” roles through hydrophobic interaction. The whole structure analysis demonstrates that mutagenesis comes from the pockets, which will destabilize cavity environment, causing obvious fluctuations and leading to low ligand-affinity and ligand escape. These simulation results interpret some experimental phenomena and provide further structural informations that are useful in drug design based on Aryl hydrocarbon Receptor. |
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