Computational Insights into the Mechanism of Ligand Unbinding and Selectivity of Estrogen Receptors
Computational Insights into the Mechanism of Ligand Unbinding and Selectivity of Estrogen Receptors
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对雌激素受体配体解结合和选择性机制的计算见解
DOI：
10.1021/jp903785h
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发表时间：
2009-07-30
影响因子：
3.3
通讯作者：
Jiang, Hualiang
中科院分区：
文献类型：
--
作者：
Shen, Jie;Li, Weihua;Jiang, Hualiang
雌激素受体（ER）属于核受体超家族，迄今已鉴定出两种亚型，ER α和ER β。ER α和ER β的功能和受体表达的差异使得寻找高选择性的亚型特异性配体成为研究热点。然而，这两种亚型高度同源，并且在配体结合口袋中仅两个残基不同。因此，配体选择性的机制已成为寻找ER亚型选择性配体的重要问题。在这项研究中，操纵分子动力学模拟进行了调查的两个选择性ER β配体从ER α和ER β的结合口袋的解结合途径，这表明，H11螺旋和H7类似于H8环之间的途径是最有可能的配体逃逸。然后计算配体沿着该途径解结合的平均力势，以深入了解配体解结合能量学的分子基础，并找到配体选择性的线索。结果表明，ER α/ER β中的His 524/475在配体解结合过程中充当“看门人”。特别是，类似于ER β的H8环的H7作为极性“传递器”，控制配体从结合位点解结合，并有助于配体选择性。最后，从动力学角度讨论了ER亚型配体选择性的机制，并提出了提高ER β配体选择性的建议。这些发现可能有助于高选择性ER β配体的合理设计。
Estrogen receptors (ER) belong to the nuclear receptor superfamily, and two subtypes, ER alpha and ER beta, have been identified to date. The differentiated functions and receptor expressions of ER alpha and ER beta made it attracted to discover subtype-specified ligands with high selectivity. However, these two subtypes are highly homologous and only two residues differ in the ligand binding pocket. Therefore, the mechanism of ligand selectivity has become an important issue in searching selective ligands of ER subtypes. In this study, steered molecular dynamics simulations were carried out to investigate the unbinding pathways of two selective ER beta ligands from the binding pocket of both ER alpha and ER beta, which demonstrated that the pathway between the H11 helix and the H7 similar to H8 loop was the most probable for ligand escaping. Then potentials of mean force for ligands unbinding along this pathway were calculated in order to gain insights into the molecular basis for energetics of ligand unbinding and find clues of ligand selectivity, The results indicated that His524/475 in ER alpha/ER beta acted as a "gatekeeper" during the ligand unbinding. Especially, the H7 similar to H8 loop of ER beta acted as a polar "transmitter" that controlled the ligand unbinding from the binding site and contributed to the ligand selectivity. Finally, the mechanism of ligand selectivity of ER subtypes was discussed from a kinetic perspective and suggestions for improving the ligand selectivity of ER beta were also presented. These findings could be helpful for rational design of highly selective ER beta ligands.