雌激素受体α36亚型配体结合区的结构模建、优化及验证

Homology modeling,refining and validating of estrogen receptor α36

目的雌激素受体(estrogen receptor,ER)参与多种重要的体内生理过程,是一个重要的受体家族。新近发现的雌激素受体α36亚型(ER-α36)通过新的作用机制调节体内功能,对其进行开拓性的研究具有重要意义。方法利用已知的ER-α36序列以及两个典型的ER-α66配体结合区的晶体结构,通过同源模建的方法构建了ER-α36配体结合区的结构模型,并采用分子动力学模拟与分子对接等方法对其合理性进行了初步验证。结果与结论 ER-α36配体结合区与传统的ER-α66相比具有显著差异,蛋白整体结构缺失四段α螺旋,口袋开放性增加且柔性提高。这些特征导致配体结合特征发生变化。雌二醇、4-羟基-他莫昔芬、genistein和G-1等已知调控分子与ER-α36的对接分析,进一步验证和解释了已报道的生物实验数据。本研究所建立的ER-α36的同源模建模型具有较好的可靠性与准确性,为进一步发现和研究新的选择性ER-α36调控分子和药物奠定了基础。

Estrogen Receptors （ERs） are involved in multiple physiological processes. Modulators targeting ER have wide clinical application. New discovered splicing variant ER-α36 is capable of mediating cell sig- nals through pathways different from traditional ERs, foreseeing its research and development prospect. Utili- zing the known sequence of ER-α36 and two typical ER-α66 ligand binding domain （LBD） crystal struc- tures, the author built and optimized the homology model of ER-α36 LBD. The structural difference between ER-α36 and ER-α66 results the lack of four α helices, binding pocket opening-up and increased structural flexibility. Docking calculation of known ligands, including 17β-estradiol, 4-hydroxy-tamoxifen, Genistein and G-1 into modeled structure＇s pocket,interpreted other lab＇s published experiment results. The ER-α36 homology model built in this research is precise and reliable, serving as a fundament for further designing and screening of selective ligand against ER-α36.