Simulations reveal increased fluctuations in estrogen receptor-alpha conformation upon antagonist binding
Simulations reveal increased fluctuations in estrogen receptor-alpha conformation upon antagonist binding
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DOI：
10.1016/j.jmgm.2016.08.009
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发表时间：
2016-09-01
影响因子：
2.9
通讯作者：
Ng, Ho Leung
中科院分区：
文献类型：
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作者：
Ng, Ho Leung
分子动力学（MD）模拟已被用于模拟雌激素受体- α (er - α)在与天然激动剂17 β -雌二醇（E2）和乳腺癌药物和拮抗剂4-羟他莫昔芬（OHT）的活性代谢物结合时结构的动态波动。我们提出了迄今为止最广泛的ER-alpha的MD模拟，其中超过1 μ s的单体和二聚体形式的组合模拟。模拟结果表明，拮抗剂结合的复合物具有明显的波动，而激动剂结合的复合物则受到严格的抑制。OHT增加了位于尾部H12螺旋两侧的环的动态无序性；H12与er - α的激活状态有关。我们还报道了H12附近的波动导致OHT乙胺尾部结合模式的更大构象变化。在240 ns的模拟中，激动剂和拮抗剂的构象都是稳定的，这支持了这两种状态之间没有过渡或过渡到中间状态的假设。H12在OHT结合构象中的稳定位置表明，OHT稳定了一个明确的拮抗剂构象集合，而不仅仅是阻断激动剂驱动的er - α激活。同时，oht结合复合物的动态特性的增加是结合熵的潜在来源。(C) 2016 Elsevier Inc.版权所有。
Molecular dynamics (MD) simulations have been used to model dynamic fluctuations in the structure of estrogen receptor-alpha (ER-alpha) upon binding to the natural agonist 17 beta-estradiol (E2) and to the active metabolite of the breast cancer drug and antagonist, 4-hydroxytamoxifen (OHT). We present the most extensive MD simulations to date of ER-alpha, with over 1 mu s of combined simulations for the monomer and dimer forms. Simulations reveal that the antagonist-bound complex includes significant fluctuations while the agonist-bound complex is tightly restrained. OHT increases dynamic disorder in the loops located to either side of the tail H12 helix; H12 has been associated with the activation status of ER-alpha. We also report that fluctuations near H12 lead to greater conformational variation in the binding mode of the ethylamine tail of OHT. Both the agonist and antagonist conformations are stable throughout the 240 ns simulations, supporting the hypothesis that there are no transitions between these two states or into intermediate states. The stable position of H12 in the OHT-bound conformation suggests that OHT stabilizes a well-defined antagonist conformational ensemble rather than merely blocking the agonist-driven activation of ER-alpha. Simultaneously, the increased dynamic properties of the OHT-bound complex is a potential source of binding entropy. (C) 2016 Elsevier Inc. All rights reserved.