Schematic models of P-gp in the inward- and outward-facing conformations. The predicted models of human P-gp in the open (A) (33) and closed (B) (34) conformations are shown. The branched lines on the extracellular loop connecting TM1 and TM2 represent the glycosylated sites. The colors highlight the TMD1 (green), NBD1 (blue), TMD2 (black), and NBD2 (red) domains. The location of residues that were mutated to cysteine to test for the effect of cross-linking between NBD1 and NBD2 (P517C/I1050C), NBD1 and TMD2 (L443C/S909C), ICL1 and ICL3 (D177C/N820C), TM segments 2 and 11 (C137/A935C) or 6 and 12 (T333C/L975C) are shown.