FIGURE 6.

Model of the IH2/IH3-NBD2 interface critical for P-gp maturation and activity. A, model of human P-gp in the open conformation (17). The locations of ICL1, ICL2, and ICL3 are shown. Some regions within the highlighted inset are expanded in B. B, segments 256–269 (ICL2), 793–818 (ICL3), and 1081–1089 (NBD2) are shown. The location of residues Phe⁷⁹³, Leu⁷⁹⁷, Trp⁸⁰³, Phe⁸⁰⁴, Leu⁸¹⁴, and Leu⁸¹⁸ (green), predicted to form a hydrophobic pocket critical for maturation, is shown in green. Cross-linking of A259C (blue) in ICL2 to W803C (green) in ICL3 inhibited activity. Residue Phe¹⁰⁸⁶ (red) has been shown previously to interact with A266C (red) (16) and, together with Tyr¹⁰⁸⁷ (red) in NBD2, is predicted to form an important part of the IH2/IH3-NBD2 network important for folding and activity of P-gp.