Chemical strategies to block quorum sensing (QS) could provide a route to attenuate virulence in bacterial pathogens. Considerable research has focused on this approach inPseudomonas aeruginosa, which uses the LuxR-type receptor LasR to regulate much of its QS network. Non-native ligands that antagonize LasR have been developed, yet we have little understanding of the mode by which these compounds interact with LasR and alter its function, as the receptor is unstable in their presence. Herein, we report an approach to circumvent this challenge through the study of a series of synthetic LasR agonists with varying levels of potency. Structural investigations of these ligands with the LasR ligand-binding domain reveal that certain agonists can enforce a conformation that deviates from that observed for other, often more potent agonists. These results, when combined with cell-based and biophysical analyses, suggest a functional model for LasR that could guide future ligand design.

中文翻译：

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LasR群体感应受体非天然激动剂的结构和生化研究揭示了LasR的L3环“向外”构象

阻止群体感应（QS）的化学策略可以提供一种减弱细菌病原体中毒力的途径。铜绿假单胞菌对此方法进行了大量研究，该方法使用LuxR型受体LasR调节其大部分QS网络。已经开发出可拮抗LasR的非天然配体，但由于受体在存在时不稳定，我们对这些化合物与LasR相互作用并改变其功能的方式了解甚少。本文中，我们报告了通过研究一系列具有不同效力水平的合成LasR激动剂来解决这一挑战的方法。对具有LasR配体结合结构域的这些配体的结构研究表明，某些激动剂可以强制实施不同于其他通常更有效的激动剂所观察到的构象。这些结果，