fig1

Figure 1. Structures of P-glycoprotein in different conformations (A) Domain organization of P-gp according to mouse residue numbering. K427 and K1072 are lysine residues of the Walker A motifs of NBD1 and NBD2, respectively. E552 and E1197 are glutamate residues of the Walker B motifs of NBD1 and NBD2, respectively. (B) Cartoon rendition of the structure of P-gp in the inward-open conformation based on the deposited mouse P-gp structure (PDB:5KPD). The inward-open conformations are defined by the separation of the NBD1 and NBD2 and the drug-binding cavity in the TMD accessible to the cytosol. The horizontal lines represent the boundary of the membrane bilayer. Color codes for individual domains are indicated. (C) Cartoon representation of P-gp in the outward-open conformation based on the cryo-EM structure of human P-gp bound with ATP (PDB:6C0V). The outward-open conformation is defined by the close contact of the two NBDs with ATP occluded in the nucleotide-binding sites and the drug-binding cavity of TMD accessible from the extracellular space