GLUTAMINE SYNTHETASE FROM MYCOBACTERIUM TB, PROTEGRIN & D-LACTATE DEHYDROGEN

结核病已重新成为全球健康问题， 抗分枝杆菌耐药菌株的增加。 发现新颖 药物靶点由于需要穿透厚厚的 分枝杆菌的细胞外膜。 然而，最近， 发现结核分枝杆菌分泌谷氨酰胺 合成酶进入其直接环境（哈特等人，1994）， 抑制这种分泌的酶会破坏正常发育 （未公布数据）。 确定中描述的结构模型 这一建议将作为药物设计的起点 结合并抑制其作用，从而提供新的治疗方法， 对抗这种疾病。 Protegrin是一种非常有效的抗生素 作为抗微生物剂和抗病毒剂两者有效的肽。 由于Protegrin的小尺寸和相对简单的结构， 提供了一个有吸引力的模板， 化学保护肽 然而，抗微生物的方法 肽区分细胞类型，并最终破坏细胞。 对入侵细胞了解甚少。 通过描述特定的 在晶格中保护蛋白单体之间的相互作用，我们 将深入了解可能的作用机制， Protegrin。 D-乳酸脱氢酶（D-LDH）是一种 膜相关呼吸酶。 它提供了不寻常的 研究结构与 在外周膜蛋白中起作用。 确定 D-LDH的三维结构将有助于理解 蛋白质-蛋白质和蛋白质-脂质相互作用， 了解外周膜蛋白。

Tuberculosis has re-emerged as a global health concern due to a rise in anti-Mycobacterial drug-resistant strains. Discovery of novel drug targets are complicated by the need to penetrate the thick cellular envelop of Mycobacteria. However, it has been recently discovered that Mycobacterium tuberculosis secretes Glutamine Synthetase into its immediate environment (Harth et al. 1994) and that inhibition of this secreted enzyme disrupts normal development (unpublished data). Determining the structural models described in this proposal will serve as a starting point for the design of drugs that bind to and inhibit its action, hence providing new therapies to combat this disease. Protegrin is a remarkably potent antibiotic peptide, effective as both an antimicrobial and an antiviral agent. Given the small size and relatively simple structure of protegrin, it provides an attractive template for designing potentially useful chemoprotective peptides. However, the methods by which antimicrobial peptides discriminate between cell types, and ultimately destroy an invading cell is poorly understood. By characterizing specific interactions between protegrin monomers in the crystal lattice, we will gain insight into understand the possible mechanisms of action for protegrin. D-lactate dehydrogenase (D-LDH) is a membrane-associated respiratory enzyme. It provides unusual opportunity for studying the relationship between structure and function in a peripheral membrane protein. Determining the three-dimensional structure of D-LDH will help understanding the protein-protein and protein-lipid interactions in, the poorly understood peripheral membrane proteins.