Browsing by Subject "Lethal Factor"

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    Structural Biology for Drug Design: Applications in Two Systems
    (2016-08) Maize, Kimberly
    Two projects comprise this dissertation; both are focused on using the technique of protein X-ray crystallography to understand the molecular interactions that small molecules make with proteins and the subsequent exploitation of these interactions to design better substrate or inhibitor molecules. The human Histidine Triad Nucleotide Binding Proteins (hHints) are a family of nucleotide phosphoramidases and acyl nucleotide hydrolases, coming to the forefront of research interest due to the role of hHint1 in the activation of sofosbuvir, the blockbuster Hepatitis C treatment. In the hHint project, protein-ligand complexes are examined in order to establish a structural reaction trajectory, including the first captured covalent intermediate for this enzyme, and to describe a general strategy for designing a prodrug moiety that will be activated by hHint1. The Lethal Factor (LF) component of the tripartite toxin produced by Bacillus anthracis is a zinc metalloproteinase. To date, there is no approved inhibitor of this protein for the treatment of anthrax infection partially due to difficulty in obtaining selectivity over endogenous metalloproteinases. A series of hydroxamate-containing inhibitors revealed that Domain 3 of LF is responsive to the molecule in the active site and that certain states of Domain 3 may be energetically favorable to target. Furthermore, a ligand-induced extension of the canonical binding area was discovered, paving the way for the development of more specific LF inhibitors.