Bile acids are signaling molecules with critical roles in cholesterol and lipid metabolism, achieved by regulating the transcriptional activity of the farnesoid X receptor (FXR, NR1H4), otherwise known as the bile acid receptor. Modifications to the C6 position of the steroidal core yield bile acid derivatives with 100x improved potency over endogenous bile acids. Prevailing hypotheses suggested increased binding affinity for FXR as the driver for this activity enhancement. Our experimental results contradict this suggestion, motivating us to investigate the underlying mechanisms of enhanced ligand activity. We combined functional assays with over 200 microseconds of simulations, revealing an unexpected role for helix 5 in the allosteric signaling of obeticholic acid (OCA). We uncovered dynamic coupling between adjacent helices 5 and 7, which is uniquely enhanced by the bile acid modification. Ultimately, the enhanced potency of the bile acid analog can be traced to its effect on FXR dynamics. In addition to identifying a previously unknown mechanistic role for helix 5-helix 7 coupling in FXR, these results emphasize the inextricable linkage between the activity of nuclear receptor ligands and their effects on receptor dynamics.

中文翻译：

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核受体中增强的动态偶联是配体活性的基础。


胆汁酸是在胆固醇和脂质代谢中起关键作用的信号分子，通过调节法呢醇 X 受体（FXR，NR1H4）（也称为胆汁酸受体）的转录活性来实现。对甾体核心 C6 位置的修饰产生胆汁酸衍生物，其效力比内源性胆汁酸高 100 倍。普遍的假设表明，FXR 的结合亲和力增加，这是这种活性增强的驱动力。我们的实验结果与这一建议相矛盾，促使我们研究增强配体活性的潜在机制。我们将功能测定与超过 200 微秒的模拟相结合，揭示了螺旋 5 在奥贝胆酸 （OCA） 变构信号传导中的意想不到的作用。我们发现了相邻螺旋 5 和 7 之间的动态耦合，这种耦合通过胆汁酸修饰而独特地增强。最终，胆汁酸类似物的增强效力可以追溯到它对 FXR 动力学的影响。除了确定了螺旋 5-螺旋 7 偶联在 FXR 中以前未知的机制作用外，这些结果还强调了核受体配体的活性与其对受体动力学的影响之间密不可分的联系。