The long-range objective of this research program is to study the structure and function of bacterial ATP-binding cassette-type transport systems (ABC transporters) and their protein components. Structural analysis, using X-ray crystallographic technique, will focus on two components, including several binding proteins that confer the solute specificity of the transporter and chemotaxis as well and the homodimer of the ATPase-hydrolyzing subunits located at the cytoplasmic surface of the membrane. The structures of the dipeptide-binding protein with bound dipeptides may provide fruitful leads in the development of antibacterial drugs (including impermeant peptidomimetric drugs) that exploit the broad specificity of the transporter for delivery and bioactivity. Crystallization of an entire ABC transporter in a transition state will be attempted. Using crystallographic, mutagenic, and biochemical techniques, fundamental investigation of the features of protein-ligand recognition will also be pursued. Transport processes perform a vital function in the life of a cell by maintaining a relative constancy of the intracellular environment and regulating the entrance and exit of various substances necessary for metabolic activity. Chemotaxis is important for the survival (and control) of microorganisms since interaction with the environment depends largely on the ability to respond to stimuli. Beside active transport, the ABC transporters are also involved in signal transduction, protein secretion, antigen presentation, drug and antibiotic resistance, bacterial pathogenesis and sporulation. Several human diseases have been traced to ABC proteins, including cystic fibrosis, hyperinsulinemia, and macular dystrophy. Because several of the substrates of the bacterial ABC transporters are also virulence factors, agents that confer antibiotic resistance, or cellular defense factors on pathogenic bacteria are a growing threat to public health.
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