PDF(Pubmed)
Abstract：
Nuclear receptors are ligand-activated transcription factors that can often be useful drug targets. Unfortunately, ligand promiscuity leads to two-thirds of receptors remaining clinically untargeted. PXR is a nuclear receptor that can be activated by diverse compounds to elevate metabolism, negatively impacting drug efficacy and safety. This presents a barrier to drug development because compounds designed to target other proteins must avoid PXR activation while retaining potency for the desired target. This problem could be avoided by using PXR antagonists, but these compounds are rare, and their molecular mechanisms remain unknown. Here, we report structurally related PXR-selective agonists and antagonists and their corresponding co-crystal structures to describe mechanisms of antagonism and selectivity. Structural and computational approaches show that antagonists induce PXR conformational changes incompatible with transcriptional coactivator recruitment. These results guide the design of compounds with predictable agonist/antagonist activities and bolster efforts to generate antagonists to prevent PXR activation interfering with other drugs.
摘要：
核受体是配体激活的转录因子,其通常可以是有用的药物靶标。不幸的是,配体混杂导致三分之二的受体在临床上仍未靶向。PXR是一种核受体，可以被多种化合物激活以提高新陈代谢，负面影响药物疗效和安全性。这对药物开发提出了障碍,因为设计为靶向其他蛋白质的化合物必须避免PXR活化,同时保持对所需靶标的效力。这个问题可以通过使用PXR拮抗剂来避免，但是这些化合物很少见，它们的分子机制仍然未知。这里,我们报道了结构相关的PXR选择性激动剂和拮抗剂及其相应的共晶结构来描述拮抗和选择性的机制.结构和计算方法表明拮抗剂诱导与转录共激活因子募集不相容的PXR构象变化。这些结果指导具有可预测的激动剂/拮抗剂活性的化合物的设计,并支持产生拮抗剂以防止PXR活化干扰其它药物的努力。
