Insights into ligand selectivity in estrogen receptor isoforms: Molecular dynamics simulations and binding free energy calculations
Insights into ligand selectivity in estrogen receptor isoforms: Molecular dynamics simulations and binding free energy calculations
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深入了解雌激素受体亚型的配体选择性：分子动力学模拟和结合自由能计算。
DOI：
10.1021/jp710029r
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发表时间：
2008-03-06
影响因子：
3.3
通讯作者：
Jiang, Hualiang
中科院分区：
文献类型：
--
作者：
Zeng, Juan;Li, Weihua;Jiang, Hualiang
雌激素受体α (erα)和β (erβ)是配体激活的转录因子，在某些组织中具有不同的生理功能和差异表达。ERbeta的配体结合域与ERalpha的序列同源性为58%。而在结合袋中，只有两个相对残基取代。活性位点的高度相似性是设计选择性雌激素受体调节剂的巨大挑战。乙二β被证明与几种疾病有关。为了了解erβ选择性的分子基础，对erα和erβ配合物进行了分子动力学模拟。我们的模拟揭示了内质网活性位点的构象变化以及与配体亲和力的差异。ERalpha Met421的Sdelta原子与配体的乙腈基氮原子之间的静电斥力导致不利于结合。斥力导致ERalpha Met421侧链的构象改变，从而改变了Leu346和Phe425的构象。这些残基的变化扩大了结合腔的体积，导致配体的结合不稳定。此外，ERbeta Met336相对于相应的残基ERalpha Leu384与配体形成更多的疏水接触。结合自由能的分析结果与之前的实验结果相吻合。最后，自由能分解明显地反映了关键残基的贡献。本研究结果有助于解释erβ选择性的机制，并可用于亚型选择性配体的设计。
Estrogen receptor alpha (ERalpha) and beta (ERbeta) are ligand activated transcription factors that have different physiological functions and differential expression in certain tissues. The ligand binding domain of ERbeta shares 58% sequence identity with that of ERalpha. However, in the binding pocket there are only two relative residue substitutions. This high similarity at the active site is a great challenge for designing selective estrogen receptor modulators. ERbeta is shown to be related to several diseases. To understand the molecular basis of ERbeta selectivity, molecular dynamics simulations were carried out for both ERalpha and ERbeta complexes. Our simulations revealed the conformational changes at the active site of the ERs and the difference of affinity with ligand. The electrostatic repulsion between the Sdelta atom of ERalpha Met421 and the acetonitrile group nitrogen atom of the ligand led to unfavorable binding. The repulsion resulted in the conformational change of the side chain of ERalpha Met421, which changed the conformation of both Leu346 and Phe425. These residues changes expanded the volume of binding cavity, which led to unstable binding of the ligand. In addition, ERbeta Met336 formed more hydrophobic contacts with the ligand relative to corresponding residue ERalpha Leu384. Furthermore, the binding free energy analysis was shown to be correlated with the previous results determined by experiment. At last, free energy decomposition evidently indicated the contributions of key residues. The present results could help explain the mechanism of ERbeta selectivity and may be considered in the design of subtype-selective ligands.