Mechanism and Inhibition of Anthrax Lethal Factor

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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.