Inhalation of Bacillus anthracis
spores leads to a frequently fatal
systemic infection that is largely due to a complex of three toxic
proteins produced by the bacteria. Edema Factor (EF), an adenylyl
cyclase, catalyzes the production of cAMP from ATP and causes tissue
swelling. Lethal Factor (LF) is a zinc-metalloproteinase that
cleaves most mitogen-activated protein kinase kinase (MKK) enzymes near
their N-terminus and kills macrophages. Both toxins are
transported into the host cell cytosol by the Protective Antigen
Protein (PA). Sequence decomposition has been used in our
research to: identify conserved residues and likely interacting protein
sites, yield conserved functional areas that differ from mammalian
proteins with similar activities and to guide design of novel
inhibitors to complex formation (EF-PA, LF-PA) or the catalytic
activities of LF and EF.
Ongoing Research
Currently,
our collective group is involved in:
Analysis of each of the toxins
sequence decomposition
catalytic domain
available crystal structures (bound and
unbound)
assembly of the toxins to PA
Design and Synthesis of Inhibitors
synthetic precursors/variants of PGE2-Imidazole
Docking of inhibitors to catalytic sites
AutoDock docking
FlexX docking
HINT! scoring
Library screening to identify other potential
inhibitors
Experimental cell culture assays
This Page last Updated 20 July 2006 by David Power.
