Mechanism and Inhibition of Anthrax Lethal Factor

炭疽致死因子的作用机制及抑制作用

• 批准号: 312629-2013
• 负责人: Siemann, Stefan
• 金额: $ 2.48万
• 依托单位: Laurentian University of Sudbury
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=571787
• 关键词: Mechanism; Inhibition; Anthrax; Lethal; Factor

Zinc is an essential element, and an indispensable constituent of more than 300 enzymes involved in many critical biological processes. My research program seeks to understand how these enzymes work on the molecular level. Our primary focus of study is the anthrax lethal factor (LF), a zinc-dependent metalloenzyme, which constitutes one of the three components of the anthrax toxin. One of the other components of this toxin is termed protective antigen (PA). PA is a pore-forming protein, which allows LF to enter the host cell cytoplasm where it exerts its deleterious action. The mechanism underlying LF's metalloenzyme activity is still unknown. In addition, a complete picture of how PA mediates the entry of LF into the host cell (a quintessential step for toxicity) is currently lacking. The proposed work is aimed at gaining an understanding of how LF works on the molecular level, and of how interactions between PA and LF lead to the successful transit of the latter protein into the cell. In light of the general concerns regarding anthrax as an animal and human pathogen, as well as a weapon of bioterrorism, the proposed research will provide insights which may be exploited by pharmaceutical enterprises to develop drugs that would counteract the deleterious effects associated with anthrax.

锌是一种必需元素，也是参与许多关键生物过程的300多种酶的不可或缺的组成部分。我的研究计划试图在分子水平上了解这些酶是如何工作的。我们的主要研究重点是炭疽致死因子(LF)，这是一种依赖于锌的金属酶，它构成了炭疽毒素的三种成分之一。这种毒素的另一个成分被称为保护性抗原(PA)。PA是一种致孔蛋白，它允许LF进入宿主细胞细胞质，在那里发挥其有害作用。 目前，LF金属酶活性的机制尚不清楚。此外，目前还缺乏PA如何调节LF进入宿主细胞的完整画面(这是毒性的典型步骤)。这项拟议的工作旨在了解LF在分子水平上是如何工作的，以及PA和LF之间的相互作用如何导致后者成功地转运到细胞内。鉴于人们普遍关注炭疽作为动物和人类的病原体以及生物恐怖主义的武器，拟议的研究将提供一些见解，制药企业可以利用这些见解来开发可抵消炭疽相关有害影响的药物。