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, ABCBl) drug pump. Homology models based on the crystal structures of mouse and Caenorhabditis etegans P-gps show extensive contacts between intracellular loop 2 (ICL2, in the first transmembrane domain) and the second nucleotide-binding domain. Human P-gp modeled on these P-gp structures yields 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. [ABSTRACT FROM AUTHOR]