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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Molecular dynamics and free energy studies on the Drosophila melanogaster and Leptinotarsa decemlineata ecdysone receptor complexed with agonists: Mechanism for binding and selectivity
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Molecular dynamics and free energy studies on the Drosophila melanogaster and Leptinotarsa decemlineata ecdysone receptor complexed with agonists: Mechanism for binding and selectivity

机译:对果蝇的分子动力学和自由能研究与激动剂复合的果蝇和瘦曲霉素和瘦曲霉素癸酸酯受体:结合和选择性的机制

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摘要

The ecdysone receptor is a nuclear hormone receptor that plays a pivotal role in the insect metamorphosis and development. To address the molecular mechanisms of binding and selectivity, the interactions of two typical agonists Ponasterone A and 20-Hydroxyecdysone with Drosophila melanogaster (DME) and Leptinotarsa decemlineata ecdysone (LDE) receptors were investigated by homology modeling, molecular docking, molecular dynamic simulation, and thermodynamic analysis. We discover that 1) the L5-loop, L11-loop, and H12 helix for DME, L7-loop, and L11-loop for LDE are more flexible, which affect the global dynamics of the ligand-binding pocket, thus facilitating the ligand recognition of ecdysone receptor; 2) several key residues (Thr55/Thr37, Phe109/Phe91, Arg95/Arg77, Arg99/Arg81, Phe108/Leu90, and Ala110/Val92) are responsible for the binding of the proteins; 3) the binding-free energy is mainly contributed by the van der Waals forces as well as the electrostatic interactions of ligand and receptor; 4) the computed binding-free energy difference between DME-C1 and LDE-C1 is -4.65 kcal/mol, explains that C1 can form many more interactions with the DME; 5) residues Phe108/Leu90 and Ala110/Val92 have relatively position and orientation difference in the two receptors, accounting most likely for the ligand selectivity of ecdysone receptor from different orders of insects. This study underscores the expectation that different insect pests should be able to discriminate among compounds from different as yet undiscovered compounds, and the results firstly show a structural and functional relay between the agonists and receptors (DME and LDE), which can provide an avenue for the development of target-specific insecticides.
机译:蜕皮受体是一种核激素受体,在昆虫变态和发育中起着枢轴作用。为了解决结合和选择性的分子机制,通过同源性建模,分子对接,分子动态模拟,研究了两种典型激动剂痘剂A和20-羟基迪克松的相互作用和20-羟基粥样液与果蝇(DME)和Leptinotarsa recemlineata(LEPTINOTARSA redemlineATONA受体。热力学分析。我们发现1)L5环,L11环和用于DME,L7环和L11环的H12螺旋更加柔韧,这影响了配体粘合口袋的全球动态,从而促进配体识别蜕膜受体; 2)几个关键残留物(Thr55 / thr37,PHE109 / PHE91,ARG95 / ARG77,ARG99 / ARG81,PHE108 / LEU90和ALA110 / VAL92)负责蛋白质的结合; 3)无粘合能量主要由Van der WaaS力以及配体和受体的静电相互作用贡献; 4)DME-C1和LDE-C1之间的无结合能量差为-4.65kcal / mol,解释说C1可以形成与DME的更多相互作用; 5)残留物PHE108 / Leu90和Ala110 / Val92具有相对位置和两个受体中取向差异,最可能来自不同昆虫的蜕皮受体的配体选择性。这项研究强调了不同害虫应该能够在不同的化合物中区分不同害虫的预期,并且结果首先显示了激动剂和受体(DME和LDE)之间的结构和功能继电器,这可以提供大道靶特异性杀虫剂的发展。

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