Solution NMR Studies of an ATP-Binding Cassette

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DESCRIPTION (provided by applicant): The ATP-binding cassette (ABC) is the signature module of the ABC transporter superfamily. ABC transporters comprise a significant percentage of all non-viral genomes and transport a variety of important cargos, including ions, amino acids, lipids, sugars and proteins, across cell and organelle membranes. The ABC transporters are associated with a number of diverse and critical pathologies, such as multi-drug resistance (MDR) and cystic fibrosis. ATP-binding cassettes are the energy generating motor domain of the ABC transporters but their mechanism of ATP hydrolysis and mechanochemical energy transduction is poorly understood. Recent crystallographic studies suggest that ATP-induced conformational changes in ABCs are likely to be the crucial coupling mechanism between ATP hydrolysis and solute translocation. The present fellowship proposal will apply a wide array of powerful solution nuclear magnetic resonance (NMR) techniques to delineate ATP-induced conformational and dynamic changes in the ABC domain (MJ1267) of the branched amino acid transporter from a hyperthermophilic archaebacterium. Similar studies will be carried out in a variety of mutants to establish the relationship between ATP-induced conformational changes, the mechanism of ATP-catalysis and molecular etiology of important diseases. Detailed structural and dynamic information gleaned from the proposed studies will broaden our fundamental understanding of ATP-binding cassette function and contribute essential knowledge and tools to the structure-based drug design for cystic fibrosis.