Department of Pharmacology and Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Department of Chemistry, University of Wisconsin, Madison, WI 53706, USA.
Mol Microbiol. 2018 May;108(3):240-257. doi: 10.1111/mmi.13930. Epub 2018 Mar 11.
Pseudomonas aeruginosa is an opportunistic pathogen that uses the process of quorum sensing (QS) to coordinate the expression of many virulence genes. During quorum sensing, N-acyl-homoserine lactone (AHL) signaling molecules regulate the activity of three LuxR-type transcription factors, LasR, RhlR and QscR. To better understand P. aeruginosa QS signal reception, we examined the mechanism underlying the response of QscR to synthetic agonists and antagonists using biophysical and structural approaches. The structure of QscR bound to a synthetic agonist reveals a novel mode of ligand binding supporting a general mechanism for agonist activity. In turn, antagonists of QscR with partial agonist activity were found to destabilize and greatly impair QscR dimerization and DNA binding. These results highlight the diversity of LuxR-type receptor responses to small molecule agonists and antagonists and demonstrate the potential for chemical strategies for the selective targeting of individual QS systems.
铜绿假单胞菌是一种机会致病菌，它利用群体感应（QS）过程来协调许多毒力基因的表达。在群体感应过程中，N-酰基高丝氨酸内酯（AHL）信号分子调节三种 LuxR 型转录因子 LasR、RhlR 和 QscR 的活性。为了更好地理解铜绿假单胞菌 QS 信号的接收，我们使用生物物理和结构方法研究了 QscR 对合成激动剂和拮抗剂的反应机制。与合成激动剂结合的 QscR 结构揭示了一种新的配体结合模式，支持激动剂活性的一般机制。反过来，具有部分激动剂活性的 QscR 拮抗剂被发现会破坏 QscR 二聚体形成和 DNA 结合，并使其严重受损。这些结果突出了 LuxR 型受体对小分子激动剂和拮抗剂的反应多样性，并证明了针对单个 QS 系统的化学策略的潜力。
