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. Multidrug resistance is a serious medical problem and presents a major challenge to the treatment of disease and the development of novel therapeutics. ABC transporters that are associated with multidrug resistance move hydrophobic drugs and lipids from the inner to the outer leaflet of the cell membrane. E.coli MsbA lipopolysaccharide (lipid A) flippase is homolog of mammalian P-glycoproteins. Different transporters are thought to have a common mechanism based on ATP binding and hydrolysis to energize the substrate translocation. The structure of MsbA in vesicles is different from that in detergent used in X-ray crystallography. Therefore, the study of MsbA conformational changes produced by ATP hydrolysis in the lipid environment is valuable, but requires methods suited for such case. Distance constraints from ESR are well up to the task. We plan to determine a critical set of such constraints to undersand better the MsbA conformational changes.
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