Abstract : We applied a focused structural genomics approach to determine the atomic resolution crystal structures of key virulence factors from high priority pathogens. In our first year we focused on proteins encoded by the B. anthracis virulence plasmid, pX01, and the setting up of a virulence factor computational data base. In the second year we expanded our efforts to include genome-encoded proteins of B. anthracis, and structural studies on proteins encoded by Variola virus, the causative agent of smallpox. In year 3 we continued work on Variola proteins, including determining the structure of an important virulence factor, N1L. We also determined the structure of a SARS virus surface protein in complex with a neutralizing antibody. We have generated a large library of expression vectors for virulence factors, as well as research quantities of pure proteins, which could readily be adapted for vaccine design. We determined the structures of 12 novel virulence factors and more than 20 Lethal Factor complex, which can be utilized for rational drug design. The accumulated structural information will generate important and testable hypotheses that will increase our understanding of the molecular mechanisms of pathogenicity, putting us in a stronger position to anticipate and react to emerging pathogens.