This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Multidrug efflix pumps interfere significantly with cancer chemotherapy and treatment of bacterial infections, by recognizing a number of structurally unrelated toxic compounds and actively extruding them from cells. Our long-term goal is to elucidate the structures and fundamental mechanisms that give rise to drug recognition and extrusion in multidrug transporters. Recently, we have crystallized several AcrB mutants. Studying on those mutants is thought to important for uncovering the mechanism of proton translocation in the pump. We will determine their x-ray structures with different ligands. AcrB exists as a complex with a periplasmic membrane fusion protein, AcrA. These two proteins presumably interact in the periplasm. The role of AcrA, which is absolutely required for transport, is still not known. To understand the mechanism of multidrug transport, the x-ray structure of the AcrAB complex is essential. We have co-crystallized the AcrB (native) and AcrA (with 6-his tag) efflux proteins. Visualizing the structure of this complex by crystallography will provide us direct information about the mechanism of drug extrusion.
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