This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have several projects investigating the structure and function of key enzymes and other virulence factors involved with viral and bacterial pathogenesis. Our recent structure determination of Norwalk virus polymerase replication complexes reveal several novel features that demand further structural work to determine more precisely the mechanisms underlying catalysis and inhibition in this key target for antiviral drug development. Our recent structure determination of receptor-binding fragments from Clostridium difficile toxins bound to carbohydrate receptors showed for the first time the structural basis underlying receptor recognition. Further structural work is needed in this system to define the elements underlying the specificity and avidity of carbohydrate recognition that will provide the basis for developing novel treatments for C. difficile infections. Newer projects on enzymes important for the biosynthesis of cell wall carbohydrates in Mycobacterium tuberculosis have yielded crystals that may need MAD or SAD phasing to assist with structure determination.
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