STRUCTURAL STUDIES OF THE MYCOBACTERIUM ESX-1 SECRETION SYSTEM

该子项目是利用 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来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 结核菌M.结核病，需要ESX-1分泌系统的毒力。该系统在致病性分枝杆菌中是保守的，包括M。marinum。了解ESX-1分泌系统的组分对于了解分枝杆菌对宿主细胞的致病作用至关重要。ESX-1分泌系统的几种组分已经被鉴定，它们的分子作用正在深入研究中。本研究主要集中在M. marinum，命名为Mh3881c，其从分枝杆菌的胞质溶胶进入宿主巨噬细胞，在那里发挥其破坏性作用。蛋白质在侵入宿主细胞之前经历周质蛋白酶的加工，并且这种加工对于其毒性和病原体的毒力是必需的。这种毒素或其同系物的结构尚不清楚。确定这种蛋白质及其复合物的结构对于揭示其功能将是非常宝贵的，并可能提供如何通过小分子抑制剂规避其毒性的线索。

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 tuberculosis pathogen, M. tuberculosis, requires the ESX-1 secretion system for virulence. This system is conserved among pathogenic mycobactria, including M. marinum. Understanding the components of the ESX-1 secretion system is critical to understanding the pathogenic effect of mycobacteria on host cells. Several components of the ESX-1 secretion system have been identified, and their molecular role is under intense study. We have focused our studies on protein of the ESX-1 pathway in M. marinum, designated Mh3881c, which travels from the cytosol of the mycobacteria into the host macrophages where it exerts its destructive effects. The protein undergoes processing by a periplasmic protease prior to invading host cells, and this processing is necessary for its toxicity and the pathogen's virulence. The structure of this toxin or its homologs is unknown. Determining the structure of this protein and its complexes will be invaluable in unraveling its function, and perhaps offer clues as to how its toxicity can be circumvented by small molecule inhibitors.