STRUCTURAL STUDIES OF BACTERIAL SIGNAL-TRANSDUCTION PROTEIN COMPLEXES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 细菌信号转导蛋白复合物的结构研究 组氨酸激酶已成为药物设计的有吸引力的新靶点，以规避革兰氏阳性病原菌的耐药性。 本研究的目的是从一个重要的双组分信号转导系统出发，对一个多结构域的跨膜组氨酸激酶及其反应调节因子的结构和功能进行研究。 提案：革兰氏阳性致病菌组氨酸激酶 对常见抗菌药物的耐药性是一种全球现象，并且已经观察到每一个主要细菌病原体组的耐药性增加。 显然需要鉴定用于开发新抗微生物剂的新靶标。 双组分系统在细菌中普遍存在，并且是病原菌用于控制广泛的细胞过程（包括毒力因子的表达和对某些抗菌剂的抗性）的复杂调节途径的中心元件。 典型的双组分系统由两种蛋白质组成：传感激酶和反应调节剂。 传感激酶监测环境信号，并通过磷酸转移反应调节反应调节因子的功能。反应调节子通常包含N-末端接收器结构域和C-末端DNA结合结构域。 受体结构域通过磷酸化从组氨酸激酶接收信号，这使得DNA结合结构域能够充当转录因子来调节某些基因的表达。 YycF（response regulator）：YycG（histidine kinase）系统在低G+C革兰氏阳性菌中高度保守，包括枯草芽孢杆菌、金黄色葡萄球菌、肺炎链球菌、化脓性链球菌和单核细胞增生李斯特菌，其中许多是人类病原体，对美国和世界范围的公共卫生构成重大威胁。 YycF：G系统是迄今为止已知的唯一对细胞活力至关重要的双组分系统，并且已被建议作为主要的抗微生物靶点并进行小分子抑制剂的开发。YycF：G系统已经被暗示在细胞壁生物发生中。 然而，目前尚不清楚YycG感测到什么信号以及信号如何在YycF：G系统中中继。

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. Structural studies of bacterial signal-transduction protein complexes Histidine kinases have been attractive new targets for drug design to circumvent drug resistance in Gram-positive pathogenic bacteria. Our research is aimed at structures and functions of a multi-domainal, membrane-spanning histidine kinase and its response regulator from an essential two-component signal transduction system. Proposal: Histidine kinase of Gram-positive pathogenic bacteria Resistance to common antimicrobial drugs is a global phenomenon, and an increase in resistance has been observed for every major group of bacterial pathogens. There is an obvious need for identification of novel targets for development of new antimicrobials. Two-component systems are ubiquitous in bacteria and are central elements of the intricate regulatory pathways utilized by pathogenic bacteria to control a wide range of cellular processes including expression of virulence factors and resistance to certain antimicrobial. A paradigmatic two-component system consists of two proteins: sensor kinase and response regulator. The sensor kinases monitor environmental signals, and modulate functions of response regulators through phosphotransfer reactions. The response regulators usually contain an N-terminal receiver domain and a C-terminal DNA-binding domain. The receiver domain receives signals from histidine kinase through phosphorylation, which enables the DNA-binding domain to act as a transcription factor to regulate expression of certain genes. YycF (response regulator):YycG (histidine kinase) system is highly conserved in the low G+C Gram-positive bacteria including Bacillus subtilis, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes and Listeria monocytogenis, many of which are human pathogens and pose significant threat on public health in the U.S. and worldwide. The YycF:G system is the only two-component system essential for cell viability known to date, and has been suggested as a prime antimicrobial target and subjected to small-molecule inhibitor developments. The YycF:G system has been implied in cell wall biogenesis. However, it is not clear what signal YycG senses and how the signal is relayed in the YycF:G system.