Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology , S-106 91 Stockholm, Sweden.
J Phys Chem B. 2012 Apr 26;116(16):4823-30. doi: 10.1021/jp300895g. Epub 2012 Apr 17.
The bioactivities of the natural steroidal estrogen 17β-estradiol (E2), the synthetic estrogen diethylstilbestrol (DES), and the phytoestrogen genistein (GEN) are intimately associated with their binding to the estrogen receptor α ligand binding domain (ERα LBD) and accordingly allostery. Molecular modeling techniques have been performed on agonists in complex with the LBD, focusing on the pivotal role of His524 modeled as the ε-tautomer and the protonated form (depending on pH). It is found that E2 binds to the active LBD with the aid of Leu525, showing existing stable patterns of an H-binding network with Glu419 via His524 in all models. The main difference seen in the effect is that the full agonists E2 and DES have higher binding energies to the protonated His524 than the partial agonists GEN and Way-169916 (W), which is in line with noted experimental transcriptional activities. In conclusion, the study demonstrates that the phytoestrogen GEN interacts differently with the LBD than what E2 and DES do, which explains the observed signaling differences.
天然甾体雌激素 17β-雌二醇（E2）、合成雌激素己烯雌酚（DES）和植物雌激素染料木黄酮（GEN）的生物活性与其与雌激素受体α配体结合域（ERα LBD）的结合以及变构作用密切相关。已经对与 LBD 结合的激动剂进行了分子建模技术研究，重点研究了模拟为 ε-互变异构体和质子化形式（取决于 pH）的关键残基 His524 的作用。研究发现，E2 在 Leu525 的辅助下与活性 LBD 结合，在所有模型中均显示出通过 His524 与 Glu419 形成的现有稳定 H 结合网络模式。观察到的主要区别在于，完全激动剂 E2 和 DES 与质子化 His524 的结合能高于部分激动剂 GEN 和 WAY-169916（W），这与已报道的转录活性一致。总之，该研究表明，植物雌激素 GEN 与 LBD 的相互作用与 E2 和 DES 不同，这解释了观察到的信号差异。
