Insights into Ligand Selectivity in Estrogen Receptor Isoforms: Molecular Dynamics Simulations and Binding Free Energy Calculations
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- 作者：Juan Zeng ; Weihua Li ; Yaxue Zhao ; Guixia Liu ; Yun Tang ; Hualiang Jiang
- 刊名：Journal of Physical Chemistry B
- 出版年：2008
- 出版时间：March 6, 2008
- 年：2008
- 卷：112
- 期：9
- 页码：2719 - 2726
- 全文大小：360K
- 年卷期：v.112,no.9(March 6, 2008)
- ISSN：1520-5207
文摘
Estrogen receptor 
(ER) and 
(ER) are ligand activated transcription factors that have differentphysiological functions and differential expression in certain tissues. The ligand binding domain of ERshares 58% sequence identity with that of ER. However, in the binding pocket there are only two relativeresidue substitutions. This high similarity at the active site is a great challenge for designing selective estrogenreceptor modulators. ER is shown to be related to several diseases. To understand the molecular basis ofER selectivity, molecular dynamics simulations were carried out for both ER and ER complexes. Oursimulations revealed the conformational changes at the active site of the ERs and the difference of affinitywith ligand. The electrostatic repulsion between the S
atom of ER Met421 and the acetonitrile group nitrogenatom of the ligand led to unfavorable binding. The repulsion resulted in the conformational change of theside chain of ER Met421, which changed the conformation of both Leu346 and Phe425. These residueschanges expanded the volume of binding cavity, which led to unstable binding of the ligand. In addition,ER Met336 formed more hydrophobic contacts with the ligand relative to corresponding residue ER Leu384.Furthermore, the binding free energy analysis was shown to be correlated with the previous results determinedby experiment. At last, free energy decomposition evidently indicated the contributions of key residues. Thepresent results could help explain the mechanism of ER selectivity and may be considered in the design ofsubtype-selective ligands.
(ER) and (ER) are ligand activated transcription factors that have differentphysiological functions and differential expression in certain tissues. The ligand binding domain of ERshares 58% sequence identity with that of ER. However, in the binding pocket there are only two relativeresidue substitutions. This high similarity at the active site is a great challenge for designing selective estrogenreceptor modulators. ER is shown to be related to several diseases. To understand the molecular basis ofER selectivity, molecular dynamics simulations were carried out for both ER and ER complexes. Oursimulations revealed the conformational changes at the active site of the ERs and the difference of affinitywith ligand. The electrostatic repulsion between the S atom of ER Met421 and the acetonitrile group nitrogenatom of the ligand led to unfavorable binding. The repulsion resulted in the conformational change of theside chain of ER Met421, which changed the conformation of both Leu346 and Phe425. These residueschanges expanded the volume of binding cavity, which led to unstable binding of the ligand. In addition,ER Met336 formed more hydrophobic contacts with the ligand relative to corresponding residue ER Leu384.Furthermore, the binding free energy analysis was shown to be correlated with the previous results determinedby experiment. At last, free energy decomposition evidently indicated the contributions of key residues. Thepresent results could help explain the mechanism of ER selectivity and may be considered in the design ofsubtype-selective ligands.