Figure 2.

Model of P-gp substrate transport. (A) In its substrate-binding conformation, consisting of two inward facing bundles of six transmembrane helices, P-gp contains a large internal cavity open to both the cytoplasm and the inner leaflet of the lipid bilayer. This large cavity (∼6000 ų), or substrate-binding pocket (SBP), comprises mostly hydrophobic and aromatic residues. Lipid-soluble P-gp substrate molecules partition into the inner leaflet of the phospholipid (PL) bilayer membrane. From the inner leaflet, the molecule travels through one of two portals, formed by helices 4/6 and 10/12, to enter the P-gp SBP. Substrate–P-gp interactions lead to the binding of two ATP molecules to the NBD. (B) The binding of ATP to the NBDs causes dimerization of the NBDs. This leads to a conformational change, resulting in an outward facing configuration. This outward facing arrangement facilitates the release of substrates into the extracellular environment or the outer leaflet of the PL bilayer, and sterically prevents the substrate from travelling into the intracellular space. Thus, P-gp acts as a unidirectional efflux pump (see Aller et al., 2009). Above broken line = outer leaflet of PL bilayer. Below broken line = inner (cytoplasmic) leaflet of PL bilayer.