Molecular Modeling of the Human P-glycoprotein Transporter Protein

Division Of Basic Sciences - Nci

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Abstract

The goal is to create an as accurate as possible atomic-scale model of the structure and functional mechanisms of the human P-glycoprotein (P-gp), membrane-bound transporter pump. P-gp is the best studied of the transporter proteins responsible for Multi-Drug Resistance (MDR), which may foil chemotherapy in a variety of cancer treatments. P-gp is a member of the ATP-binding cassette superfamily of transmembrane proteins, which usually couple the hydrolysis of Adenosine-5-TriPhosphate to the transport of smaller molecules out of the cell. The models will be used to design experimental studies to better understand the physical basis for the substrate specificity and functional mechanisms. In addition, the structural knowledge gained about the transmembrane pore of P-gp will be used to design small-molecule inhibitors, which could enhance the effectiveness of cancer chemotherapy treatments.