Data_Sheet_1_Ligand Binding Domain of Estrogen Receptor Alpha Preserve a Conserved Structural Architecture Similar to Bacterial Taxis Receptors.PDF

It remains a mystery why estrogen hormone receptors (ERs), which are highly specific toward its endogenous hormones, are responsive to chemically distinct exogenous agents. Does it indicate that ERs are environmentally regulated? Here, we speculate that ERs would have some common structural features with prokaryotic taxis receptor responsive toward environmental signals. This study addresses the low specificity and high responsiveness of ERs toward chemically distinct exogenous substances, from an evolutionary point of view. Here, we compared the ligand binding domain (LBD) of ER alpha (α) with the LBDs of prokaryotic taxis receptors to check if LBDs share any structural similarity. Interestingly, a high degree of similarity in the domain structural fold architecture of ERα and bacterial taxis receptors was observed. The pharmacophore modeling focused on ligand molecules of both receptors suggest that these ligands share common pharmacophore features. The molecular docking studies suggest that the natural ligands of bacterial chemotaxis receptors exhibit strong interaction with human ER as well. Although phylogenetic analysis proved that these proteins are unrelated, they would have evolved independently, suggesting a possibility of convergent molecular evolution. Nevertheless, a remarkable sequence divergence was seen between these proteins even when they shared common domain structural folds and common ligand-based pharmacophore features, suggesting that the protein architecture remains conserved within the structure for a specific function irrespective of sequence identity.

为何对其内源性激素具有高度特异性的雌激素受体（estrogen hormone receptors, ERs），能够响应化学结构迥异的外源性物质，这一问题至今仍是未解之谜。这是否意味着雌激素受体受环境因素调控？本研究推测，雌激素受体与响应环境信号的原核趋化受体可能存在部分共同结构特征。本研究从进化视角出发，探讨雌激素受体对化学结构各异的外源性物质所表现出的低特异性与高响应性问题。本研究将雌激素受体α（ERα）的配体结合域（ligand binding domain, LBD）与原核趋化受体的配体结合域进行比对，以验证二者的配体结合域是否存在结构相似性。有趣的是，研究观察到ERα与细菌趋化受体的结构域折叠架构具有高度相似性。针对两类受体配体分子开展的药效团建模结果显示，这些配体共享共同的药效团特征。分子对接实验表明，细菌趋化受体的天然配体同样可与人类雌激素受体产生较强相互作用。尽管系统发育分析证实两类蛋白并无亲缘关系，且二者为独立演化而来，但这提示存在趋同分子进化的可能性。尽管两类蛋白共享共同的结构域折叠架构与基于配体的药效团特征，但二者之间仍存在显著的序列分歧。这表明，即便序列同一性存在差异，蛋白质的结构架构仍会为实现特定功能而保持保守。