Szöllősi Dániel, Erdei Áron, Gyimesi Gergely, Magyar Csaba, Hegedűs Tamás
MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Budapest, 1094, Hungary.
Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, 1094, Hungary.
PLoS One. 2016 Jan 4;11(1):e0146066. doi: 10.1371/journal.pone.0146066. eCollection 2016.
Understanding of multidrug binding at the atomic level would facilitate drug design and strategies to modulate drug metabolism, including drug transport, oxidation, and conjugation. Therefore we explored the mechanism of promiscuous binding of small molecules by studying the ligand binding domain, the PAS-B domain of the aryl hydrocarbon receptor (AhR). Because of the low sequence identities of PAS domains to be used for homology modeling, structural features of the widely employed HIF-2α and a more recent suitable template, CLOCK were compared. These structures were used to build AhR PAS-B homology models. We performed molecular dynamics simulations to characterize dynamic properties of the PAS-B domain and the generated conformational ensembles were employed in in silico docking. In order to understand structural and ligand binding features we compared the stability and dynamics of the promiscuous AhR PAS-B to other PAS domains exhibiting specific interactions or no ligand binding function. Our exhaustive in silico binding studies, in which we dock a wide spectrum of ligand molecules to the conformational ensembles, suggest that ligand specificity and selection may be determined not only by the PAS-B domain itself, but also by other parts of AhR and its protein interacting partners. We propose that ligand binding pocket and access channels leading to the pocket play equally important roles in discrimination of endogenous molecules and xenobiotics.
在原子水平上理解多药结合将有助于药物设计以及调控药物代谢的策略，包括药物转运、氧化和结合。因此，我们通过研究芳基烃受体（AhR）的配体结合结构域即PAS-B结构域，探索了小分子混杂结合的机制。由于用于同源建模的PAS结构域序列同一性较低，我们比较了广泛使用的HIF-2α和一个更新的合适模板CLOCK的结构特征。这些结构被用于构建AhR PAS-B同源模型。我们进行了分子动力学模拟以表征PAS-B结构域的动态特性，并将生成的构象集合用于虚拟对接。为了理解结构和配体结合特征，我们将混杂的AhR PAS-B与其他表现出特异性相互作用或无配体结合功能的PAS结构域的稳定性和动力学进行了比较。我们详尽的虚拟结合研究，即将广泛的配体分子与构象集合进行对接，表明配体特异性和选择可能不仅由PAS-B结构域本身决定，还由AhR的其他部分及其蛋白质相互作用伙伴决定。我们提出，配体结合口袋以及通向该口袋的通道在区分内源性分子和外源性物质方面起着同等重要的作用。
