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Outward-faceing model of P-glycoprotein

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made with VMD

One of the most common mechanisms by which cancer and microbial cells develop resistance against chemotherapeutic agents is to express a large number of specialized transporter proteins in their cellular membrane that use the universal cellular energy of ATP to actively pump the drug molecules to the outside. P-glycoprotein, a prominent member of such molecular "vacuum cleaners" and responsible for multidrug resistance (MDR) in a wide variety of cancer types, accomplishes its role by undergoing large-scale structural transitions in the cellular membrane through which it effectively moves drug molecules from one side of the membrane to the other. In a recent collaborative publication in Nature with leading experimental groups at Vanderbilt and Virginia, and employing advanced molecular modeling and simulation techniques implemented in NAMD, a robust structural model was developed for the unknown outward-facing state of P-glycoprotein, allowing a full structural description of the transport cycle, and a novel mode of energy transduction. Further details of the study can be found here.