STRUCTURAL STUDIES OF BACTERIAL SIGNAL-TRANSDUCTION PROTEIN COMPLEXES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细菌信号转导蛋白复合体的结构研究 组氨酸激酶已成为革兰氏阳性致病菌耐药药物设计的新靶点。我们的研究旨在从一个基本的双组分信号转导系统出发，研究一个多结构域、跨膜的组氨酸激酶及其反应调节因子的结构和功能。 建议：革兰氏阳性病原菌的组氨酸激酶 对常见抗菌药的耐药性是一种全球现象，每一种主要细菌病原体的耐药性都有所增加。显然有必要确定新的目标，以开发新的抗菌剂。二组分系统在细菌中普遍存在，是病原菌用来控制广泛的细胞过程的复杂调控途径的核心元件，包括毒力因子的表达和对某些抗菌剂的耐药性。一个典型的双组分系统由两个蛋白质组成：传感器蛋白和反应调节蛋白。传感器激酶监测环境信号，并通过磷酸转移反应调节反应调节器的功能。反应调节子通常含有一个N-端的接收域和一个C-端的DNA结合域。受体域通过磷酸化接收来自组氨酸激酶的信号，这使得DNA结合域能够作为转录因子来调节某些基因的表达。 YycF(反应调节因子)：YycG(组氨酸激酶)系统在低G+C革兰氏阳性菌中高度保守，包括枯草杆菌、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性李斯特菌，其中许多是人类病原体，在美国和世界范围内对公共健康构成重大威胁。YycF：G系统是迄今已知的唯一对细胞存活至关重要的双组分系统，已被建议作为主要的抗菌靶点，并受到小分子抑制剂开发的影响。YycF：G系统参与了细胞壁的生物发生。然而，目前还不清楚YycG感测到什么信号，以及该信号在YycF：G系统中是如何传递的。

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.