HOLOLUXP:LUXQ

全息图：LUXQ

• 批准号: 7957300
• 负责人: Matthew B Neiditch
• 金额: $ 0.48万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957300
• 关键词: Anti-Bacterial Agents; Antibiotics; Bacteria; Binding; Bioluminescence; Cell Density; Communication; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallography; Cytoplasm; DNA; Development; Environment; Funding; Gene Expression; Grant; Institution; Ligand Binding; Light; Marines; Mediating; Membrane; Microbial Biofilms; Mind; Monitor; Mutation; Phosphoric Monoester Hydrolases; Phosphotransferases; Population; Process; Production; Regulation; Research; Research Personnel; Resistance; Resources; Signal Transduction; Signaling Molecule; Source; Structure; Synchrotrons; United States National Institutes of Health; VAI-2; Vibrio; Virulence Factors; antimicrobial; density; design; extracellular; periplasm; quorum sensing; receptor; response; sensor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The extracellular signal molecule autoinducer-2 (AI-2) mediates quorum sensing communication in diverse bacterial species. In marine vibrios, binding of AI-2 to the periplasmic receptor LuxP modulates the activity of the inner membrane sensor kinase LuxQ, transducing the AI-2 information into the cytoplasm. At low cell density, when LuxP is not bound to AI-2, LuxQ functions as a kinase, whereas at high cell density, when LuxP is bound to AI-2, LuxQ acts as a phosphatase. We have shown that Vibrio harveyi LuxP associates constitutively with LuxQ in both the presence and absence of AI-2. The 1.9 ¿¿¿ x-ray crystal structure of apoLuxP, complexed with the periplasmic domain of LuxQ, reveals that the latter contains two tandem PAS (Per/ARNT/Simple-minded) folds. Thus, although many prokaryotic PAS folds themselves bind ligands, the LuxQ periplasmic PAS folds instead bind LuxP, monitoring its AI-2 occupancy. Mutations that disrupt the apoLuxP:LuxQ interface sensitize V. harveyi to AI-2, implying that AI-2 binding causes the replacement of one set of LuxP:LuxQ contacts with another. These conformational changes switch LuxQ between two opposing enzymatic activities, each of which conveys information to the cytoplasm about the cell density of the surrounding environment. Comparison of the apo complex and holo complex (proposed here) structures will reveal AI-2-induced conformational changes, and therefore, the mechanism of AI-2 signaling regulation. Bacteria modulate gene expression in response to changes in cell density via a mechanism termed quorum sensing. This density-triggered response results in coordinated phenotypic changes within bacterial populations. Quorum sensing directs processes including virulence factor expression, biofilm development, bioluminescence, antibiotic production, and DNA exchange. Our studies will facilitate the rational design of broad-spectrum antibacterial compounds that interfere with quorum sensing. Discovery of such compounds is critical as bacteria increasingly become resistant to current antimicrobial therapies.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 细胞外信号分子自动诱导剂-2（AI-2）介导多样性细菌中的法定传感器通信。在海洋振动中，AI-2与周质接收器LUXP的结合调节了内膜传感器激酶LuxQ的活性，将AI-2信息传递到细胞质中。在低细胞密度下，当LuxP与AI-2结合时，LUXQ充当激酶，而在高细胞密度下，当LuxP与AI-2结合时，LuxQ充当磷酸酶。我们已经表明，在AI-2的存在和不存在的情况下，藤子Harveyi LuxP与LuxQ构成了构成与LuxQ的联系。与Luxq的周质结构域复合的Apoluxp的1.9€€€€€»X射线晶体结构表明，后者包含两个串联PA（PER/ARNT/ARNT/SIMPTIFE）褶皱。这是，尽管许多原核生物PAS本身会结合配体，但Luxq Pariplasmic PAS折叠折叠luxP，监测其AI-2占用率。破坏Apoluxp的突变：LuxQ接口灵敏度V. Harveyi对AI-2，这意味着AI-2结合会导致替换一组LuxP：Luxq与另一种luxQ接触。这些会议变化在两个相对的酶促活动之间切换了LUXQ，每种活动都将信息传达到有关周围环境细胞密度的细胞质中。对Apo复合物和Holo复合物（此处提出的）结构的比较将揭示AI-2诱导的构象变化，因此，AI-2信号传导调节的机理。 细菌通过称为群体传感器的机制调节基因表达，以响应细胞密度的变化。这种密度触发的响应导致细菌种群中协调的表型变化。法定人数敏感性指导过程，包括病毒因子表达，生物膜发育，生物发光，抗生素产生和DNA交换。我们的研究将促进干扰群体传感的广谱抗菌化合物的合理设计。这种化合物的发现至关重要，因为细菌越来越对当前的抗菌疗法具有抗性。