Figure 4

Model of Fluo-4 transport. The docking of substrates in the PfMDR1 binding pocket is influenced by the size, charge and polarity of local amino acids. Asparagine (N) and aspartic acid (D) are both polar, hydrophilic and small in volume. While N is an amide and uncharged, D is acidic and negatively charged. a For parasites containing the PfMDR1 N1042 polymorphism, the intrinsically negatively charged Fluo-4 gets transported from the cytoplasm into the digestive vacuole (DV) where it accumulates. b In the presence of PfMDR1 N1042D, which adds a negative charge to the binding pocket, Fluo-4 does not get transported by PfMDR1 and no Fluo-4 accumulation is detected in the DV. c Fluo-4 transport is abolished through the addition of the Pgp inhibitor tariquidar (TQ), which does not alter the substrate binding but prevents ATP hydrolysis and therefore the conformational change that is necessary for substrate dislocation.