Hexapeptide repeat proteins display tandem repeated copies of a six- residue amino acid sequence generally described as (LIV)-(GAED)-X2- (STAV)-X. These proteins display a unique three-dimensional structural motif termed a Left-Handed Parallel beta Helix (LbetaH). Hexapeptide enzymes frequently function as acyltransferases in a variety of processes, including bacterial cell wall biosynthesis, amino acid metabolism and antibiotic inactivation. In this proposal, the three- dimensional structure of at least two members of the largest class of these proteins, the hexapeptide acetyltransferases, will be determined by x-ray crystallography in the presence and absence of ligands. This structural information will be combined with steady state kinetic data in order to define the order of addition of substrates, the identity of catalytically important functional groups and the chemical mechanism of action of these enzymes. This information will be used to characterize the function of this newly recognized superfamily of enzymes and to provide a structural and mechanistic framework for the design of antibiotics directed against bacterial pathogens.
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