STRUCTURAL STUDIES OF ANTHRAX LETHAL TOXIN

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this work is to determine the atomic-level mechanisms of intoxication by Anthrax Lethal Toxin, and to facilitate structure-based drug design of anti-toxins. The two toxin components are Protective Antigen (PA) and Lethal Factor (LF). Based on our structure of the water-soluble heptamer of PA63 we have formulated a specific hypothesis of pH-induced conformational change leading to the creation of a membrane-spanning beta-barrel. We recently completed the crystal structure of LF and determined the structure in complex with one of its intracellular targets, MAP kinase kinase-2 (MAPKK). We propose to extend this work by determining the high resolution structures of LF in complex with MAPKK-derived peptides and inhibitors, and the membrane inserted structure of PA63.