文献类型：期刊文献

英文题名：Computational Insights into the Mechanism of Ligand Unbinding and Selectivity of Estrogen Receptors

作者：Shen, Jie[1];Li, Weihua[1];Liu, Guixia[1];Tang, Yun[1];Jiang, Hualiang[1,2]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 200031, Peoples R China

年份：2009

卷号：113

期号：30

起止页码：10436

外文期刊名：JOURNAL OF PHYSICAL CHEMISTRY B

收录：;EI(收录号：20093112235477);WOS:【SCI-EXPANDED(收录号:WOS:000268231000052)】；

基金：We thank Dr. Dave Case for his kindness to offer us the Amber10 package. This work was supported by the Program for New Century Excellent Talents in University (Grant No. NCET-08-0774), the 863 High-Tech Project (Grant No. 2006AA020404), the 111 Project (Grant No. B07023), the National Natural Science Foundation of China (Grant No. 30600785), and the Shanghai Rising-Star Program (Grant No. 07QA14016).

语种：英文

外文关键词：Molecular dynamics

摘要：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.