A Salt Bridge in Intracellular Loop 2 Is Essential for Folding of Human P-Glycoprotein

There is no high-resolution structure of the human P-glycoprotein (P-gp; ABCB1) drug pump. Homology models based on the crystal structures of mouse and C. elegans P-gps show extensive contacts between ICL2 (in the first transmembrane domain) and the second nucleotide-binding domain. Human P-gp modeled on these P-gp structures yield different ICL2 structures. Only the model based on the C. elegans P-gp structure predicts the presence of a salt bridge. We show that the Glu256-Arg276 salt bridge was critical for P-gp folding.