Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms
Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms
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DOI：
10.1016/j.cotox.2017.01.011
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发表时间：
2017-02-01
影响因子：
4.6
通讯作者：
Motta, Stefano
中科院分区：
文献类型：
--
作者：
Bonati, Laura;Corrada, Dario;Motta, Stefano
分子模拟为阐明AhR信号转导途径的主要阶段做出了重要贡献。尽管缺乏实验确定的AhR功能结构域的结构，来自同源系统的信息已被利用建模其结构和相互作用。AhR PASB结构域的同源模型提供了结合腔的信息，并有助于阐明配体结合的种属特异性差异。配体结合过程的分子对接模拟已经深入了解了不同激动剂、拮抗剂和选择性AhR调节剂的结合差异，并且它们在化合物的大型数据库的虚拟筛选中的应用已经允许鉴定新型AhR配体。最近可用的其他bHLH-PAS系统的蛋白质-蛋白质和蛋白质-DNA复合物的结构信息开辟了道路的AhR：ARNT二聚体结构建模和研究AhR转化和DNA结合的机制。未来的研究方向应包括蛋白质动力学的模拟，以获得更可靠的描述分子间相互作用参与信号传输。
Molecular modeling has given important contributions to elucidation of the main stages in the AhR signal transduction pathway. Despite the lack of experimentally determined structures of the AhR functional domains, information derived from homologous systems has been exploited for modeling their structure and interactions. Homology models of the AhR PASB domain have provided information on the binding cavity and contributed to elucidate species-specific differences in ligand binding. Molecular Docking simulations of the ligand binding process have given insights into differences in binding of diverse agonists, antagonists, and selective AhR modulators, and their application to virtual screening of large databases of compounds have allowed identification of novel AhR ligands. Recently available structural information on protein-protein and protein-DNA complexes of other bHLH-PAS systems has opened the way for modeling the AhR: ARNT dimer structure and investigating the mechanisms of AhR transformation and DNA binding. Future research directions should include simulation of the protein dynamics to obtain a more reliable description of intermolecular interactions involved in signal transmission.