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首页> 外文期刊>International Journal of Environmental Research and Public Health >Preliminary Molecular Dynamic Simulations of the Estrogen Receptor Alpha Ligand Binding Domain from Antagonist to Apo
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Preliminary Molecular Dynamic Simulations of the Estrogen Receptor Alpha Ligand Binding Domain from Antagonist to Apo

机译：从拮抗剂到Apo的雌激素受体α配体结合域的初步分子动力学模拟

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摘要

Estrogen receptors (ER) are known as nuclear receptors. They exist in the cytoplasm of human cells and serves as a DNA binding transcription factor that regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding. The human estrogen receptor comes in two forms, alpha and beta. This work focuses on the alpha form of the estrogen receptor. The ERα is found in breast cancer cells, ovarian stroma cells, endometrium, and the hypothalamus. It has been suggested that exposure to DDE, a metabolite of DDT, and other pesticides causes conformational changes in the estrogen receptor. Before examining these factors, this work examines the protein unfolding from the antagonist form found in the 3ERT PDB crystal structure. The 3ERT PDB crystal structure has the estrogen receptor bound to the cancer drug 4-hydroxytamoxifen. The 4-hydroxytamoxifen ligand was extracted before the simulation, resulting in new conformational freedom due to absence of van der Waals contacts between the ligand and the receptor. The conformational changes that result expose the binding clef of the co peptide beside Helix 12 of the receptor forming an apo conformation. Two key conformations in the loops at either end of the H12 are produced resulting in the antagonist to apo conformation transformation. The results were produced over a 42ns Molecular Dynamics simulation using the AMBER FF99SB force field.
机译：雌激素受体（ER）被称为核受体。它们存在于人类细胞的细胞质中，并作为调节基因表达的DNA结合转录因子。但是，雌激素受体还具有独立于DNA结合的其他功能。人类雌激素受体有两种形式，α和β。这项工作的重点是雌激素受体的α形式。 ERα存在于乳腺癌细胞，卵巢基质细胞，子宫内膜和下丘脑中。已经提出，暴露于DDE，DDT的代谢产物和其他农药会导致雌激素受体的构象变化。在检查这些因素之前，这项工作检查了从3ERT PDB晶体结构中发现的拮抗剂形式释放的蛋白质。 3ERT PDB晶体结构具有与抗癌药物4-hydroxytamoxifen结合的雌激素受体。在模拟之前先提取了4-羟基他莫昔芬配体，由于配体和受体之间不存在范德华接触，导致了新的构象自由。导致的构象变化暴露了受体的螺旋12旁边的co肽的结合谱线，形成apo构象。在H12任一端的环中产生两个关键构象，从而导致apo构象拮抗剂的转化。结果是使用AMBER FF99SB力场通过42ns分子动力学模拟得出的。

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