Molecular insights into quorum sensing in the human pathogen Pseudomonas aeruginosa from the structure of the virulence regulator LasR bound to its autoinducer
Molecular insights into quorum sensing in the human pathogen Pseudomonas aeruginosa from the structure of the virulence regulator LasR bound to its autoinducer
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DOI：
10.1074/jbc.m700556200
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发表时间：
2007-05-04
影响因子：
4.8
通讯作者：
Carfi, Andrea
中科院分区：
文献类型：
--
作者：
Bottomley, Matthew J.;Muraglia, Ester;Carfi, Andrea
许多革兰氏阴性细菌通过称为自诱导物的分子进行交流，以协调其种群的活动。这种通讯被称为群体感应，可以调节致病性毒力因子的产生和抗生素耐药性。铜绿假单胞菌的群体感应系统是目前研究最深入的，因为这种细菌是一种机会性人类病原体，每年导致数千名囊性纤维化患者和许多其他免疫功能低下的个体死亡。群体感应抑制剂可以减弱铜绿假单胞菌的致病性。在这里，我们提出了铜绿假单胞菌LasR配体结合域结合其自身诱导剂3-氧代-C-12-酰基高丝氨酸内酯的晶体结构。结构是对称的二聚体，每个单体表现出类似于根癌农杆菌和大肠杆菌的TraR和SdiA群体感应蛋白的α-β-α折叠。该结构被确定为1.8埃分辨率，并揭示了LasR及其自诱导剂之间的原子相互作用。LasR、TraR和SdiA的单体结构相当，但在其四级组织中显示出差异。它们的结合位点的检查显示了一些意想不到的变化，导致其结合的自诱导物的构象完全不同。我们模拟了LasR和各种群体感应抑制剂之间的相互作用，深入了解它们可能的作用机制。该结构还为群体感应抑制剂的优化或从头设计提供了平台。
Many Gram-negative bacteria communicate via molecules called autoinducers to coordinate the activities of their populations. Such communication is termed quorum sensing and can regulate pathogenic virulence factor production and antimicrobial resistance. The quorum sensing system of Pseudomonas aeruginosa is currently the most intensively researched, because this bacterium is an opportunistic human pathogen annually responsible for the death of thousands of cystic fibrosis sufferers and many other immunocompromised individuals. Quorum sensing inhibitors can attenuate the pathogenicity of P. aeruginosa. Here we present the crystal structure of the P. aeruginosa LasR ligand-binding domain bound to its autoinducer 3-oxo-C-12-acylhomoserine lactone. The structure is a symmetrical dimer, with each monomer exhibiting an alpha-beta-alpha fold similar to the TraR and SdiA quorum sensing proteins of Agrobacterium tumefaciens and Escherichia coli. The structure was determined up to 1.8- angstrom resolution and reveals the atomic interactions between LasR and its autoinducer. The monomer structures of LasR, TraR, and SdiA are comparable but display differences in their quaternary organization. Inspection of their binding sites shows some unexpected variations resulting in quite different conformations of their bound autoinducers. We modeled interactions between LasR and various quorum sensing inhibitors, yielding insight into their possible mechanisms of action. The structure also provides a platform for the optimization, or de novo design, of quorum sensing inhibitors.