An Autoinducer Analogue Reveals an Alternative Mode of Ligand Binding for the LasR Quorum-Sensing Receptor.,ACS Chemical Biology

当前位置： X-MOL 学术 › ACS Chem. Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

An Autoinducer Analogue Reveals an Alternative Mode of Ligand Binding for the LasR Quorum-Sensing Receptor.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-03-04 , DOI: 10.1021/acschembio.8b00971
Jon E Paczkowski ₁ , Amelia R McCready ₁ , Jian-Ping Cong _{1,

2} , Zhijie Li ₃ , Philip D Jeffrey ₁ , Chari D Smith ₁ , Brad R Henke ₄ , Frederick M Hughson ₁ , Bonnie L Bassler _{1,

2}

Affiliation

Bacteria use a cell-cell communication process called quorum sensing to coordinate collective behaviors. Quorum sensing relies on production and group-wide detection of extracellular signal molecules called autoinducers. Here, we probe the activity of the Pseudomonas aeruginosa LasR quorum-sensing receptor using synthetic agonists based on the structure of the native homoserine lactone autoinducer. The synthetic compounds range from low to high potency, and agonist activity tracks with the ability of the agonist to stabilize the LasR protein. Structural analyses of the LasR ligand binding domain complexed with representative synthetic agonists reveal two modes of ligand binding, one mimicking the canonical autoinducer binding arrangement, and the other with the lactone head group rotated approximately 150°. Iterative mutagenesis combined with chemical synthesis reveals the amino acid residues and the chemical moieties, respectively, that are key to enabling each mode of binding. Simultaneous alteration of LasR residues Thr75, Tyr93, and Ala127 converts low-potency compounds into high-potency compounds and converts ligands that are nearly inactive into low-potency compounds. These results show that the LasR binding pocket displays significant flexibility in accommodating different ligands. The ability of LasR to bind ligands in different conformations, and in so doing, alter their potency as agonists, could explain the difficulties that have been encountered in the development of competitive LasR inhibitors.

中文翻译：

自诱导剂类似物揭示了 LasR 群体感应受体的另一种配体结合模式。

细菌使用称为群体感应的细胞间通信过程来协调集体行为。群体感应依赖于被称为自诱导剂的细胞外信号分子的产生和群体范围内的检测。在这里，我们使用基于天然高丝氨酸内酯自诱导剂结构的合成激动剂探测铜绿假单胞菌 LasR 群体感应受体的活性。合成化合物的效力范围从低到高不等，激动剂的活性与激动剂稳定 LasR 蛋白的能力密切相关。与代表性合成激动剂复合的 LasR 配体结合域的结构分析揭示了配体结合的两种模式，一种模拟典型的自诱导物结合排列，另一种内酯头基旋转约 150°。迭代诱变与化学合成相结合，分别揭示了氨基酸残基和化学部分，它们是实现每种结合模式的关键。LasR 残基 Thr75、Tyr93 和 Ala127 的同时改变将低效化合物转化为高效化合物，并将几乎无活性的配体转化为低效化合物。这些结果表明，LasR 结合口袋在容纳不同配体方面表现出显着的灵活性。LasR 结合不同构象的配体的能力，从而改变了它们作为激动剂的效力，可以解释在开发竞争性 LasR 抑制剂时遇到的困难。LasR 残基 Thr75、Tyr93 和 Ala127 的同时改变将低效化合物转化为高效化合物，并将几乎无活性的配体转化为低效化合物。这些结果表明，LasR 结合口袋在容纳不同配体方面表现出显着的灵活性。LasR 结合不同构象的配体的能力，从而改变了它们作为激动剂的效力，可以解释在开发竞争性 LasR 抑制剂时遇到的困难。LasR 残基 Thr75、Tyr93 和 Ala127 的同时改变将低效化合物转化为高效化合物，并将几乎无活性的配体转化为低效化合物。这些结果表明，LasR 结合口袋在容纳不同配体方面表现出显着的灵活性。LasR 结合不同构象的配体的能力，从而改变了它们作为激动剂的效力，可以解释在开发竞争性 LasR 抑制剂时遇到的困难。

更新日期：2019-02-14

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南