LARMD: integration of bioinformatic resources to profile ligand-driven protein dynamics with a case on the activation of estrogen receptor
LARMD: integration of bioinformatic resources to profile ligand-driven protein dynamics with a case on the activation of estrogen receptor
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LARMD：整合生物信息资源，以雌激素受体激活案例来分析配体驱动的蛋白质动力学
DOI：
10.1093/bib/bbz141
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发表时间：
2020-11-01
影响因子：
9.5
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
--
作者：
Yang, Jing-Fang;Wang, Fan;Yang, Guang-Fu
蛋白质动力学是所有生物过程的核心，包括信号转导，细胞调节和生物催化。其中，深入探索配体驱动的蛋白质动力学有助于最佳理解蛋白质功能，这与药物发现特别相关。因此，广泛的计算工具已被设计来研究蛋白质中的重要动态信息。然而，蛋白质动力学的执行和分析仍然是具有挑战性的，由于复杂的操作步骤，特别是对于非专业人士来说，带来了很大的困难。此外，缺乏网络协议来提供在线设施来研究和可视化配体驱动的蛋白质动力学。为此，在这项研究中，我们整合了几种生物信息学工具，开发了一种名为配体和受体分子动力学（LARMD，http://chemyang.ccnu.edu.cn/ccb/server/LARMD/和http：//agroda.gzu.edu.cn：9999/ccb/server/LARMD/）的方案，用于分析配体驱动的蛋白质动力学。具体而言，以雌激素受体（ER）为例，揭示ERβ选择性机制在临床上对炎症性疾病和多种癌症的治疗起着至关重要的作用。ERβ/ERα口袋中的两个不同残基（Ile 373/Met 421和Met 336/Leu 384）是选择性的重要决定因素，尤其是ERβ的Met 336。H8螺旋、H11螺旋和H7-H8环影响选择性激动剂（WAY-244）的迁移。这些计算结果与实验结果一致。因此，LARMD提供了一个用户友好的在线协议，研究蛋白质的动态特性，并设计新的配体或定点突变。
Protein dynamics is central to all biological processes, including signal transduction, cellular regulation and biological catalysis. Among them, in-depth exploration of ligand-driven protein dynamics contributes to an optimal understanding of protein function, which is particularly relevant to drug discovery. Hence, a wide range of computational tools have been designed to investigate the important dynamic information in proteins. However, performing and analyzing protein dynamics is still challenging due to the complicated operation steps, giving rise to great difficulty, especially for nonexperts. Moreover, there is a lack of web protocol to provide online facility to investigate and visualize ligand-driven protein dynamics. To this end, in this study, we integrated several bioinformatic tools to develop a protocol, named Ligand and Receptor Molecular Dynamics (LARMD, http://chemyang.ccnu.edu.cn/ccb/server/LARMD/ and http://agroda.gzu.edu.cn:9999/ccb/server/LARMD/), for profiling ligand-driven protein dynamics. To be specific, estrogen receptor (ER) was used as a case to reveal ERβ-selective mechanism, which plays a vital role in the treatment of inflammatory diseases and many types of cancers in clinical practice. Two different residues (Ile373/Met421 and Met336/Leu384) in the pocket of ERβ/ERα were the significant determinants for selectivity, especially Met336 of ERβ. The helix H8, helix H11 and H7-H8 loop influenced the migration of selective agonist (WAY-244). These computational results were consistent with the experimental results. Therefore, LARMD provides a user-friendly online protocol to study the dynamic property of protein and to design new ligand or site-directed mutagenesis.