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. We propose to determine the structures of integral membrane proteins that cause multidrug resistance in the treatment of cancer and infectious disease. We have obtained crystals from several MDR transporters from three different families of permeases. The first class focuses on MDR transporters from the ABC transporter family. These transporters couple ATP hydrolysis to hydrophobic substrate transport. This is a continuation of our project involving the structure of the ABC lipid flippase MsbA. We have crystals of MsbA trapped in different conformational states. The second class belongs to a family of MDR H+/drug antiporters from the small drug resistance (SMR) family. We have recently determined the open conformation of this structure using help from SSRL beam lines. The third family of transporters also couples H+ gradient to drug efflux across the cell membrane and are members of the secondary transporter class. We have three classes of MDR transporter crystals that we would like screen and collect data at SSRL corresponding to these families.
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