P-gp is a 170 kD protein containing two amino acid chains, each chain consists of six transmembrane domains (TMDs) and a nucleotidebinding ndomain (NBD).The flexible structure of P-gp is responsible for its translational and rotational motions during the efflux mechanism, which also includes simultaneous variation in the NBD distance, and is related to the entrance of a molecule suitable for efflux. One proposed structure of P-gp in open conformation is based on the crystal structure of mouse P-gp with the NBDs apart was used for mapping the binding site of the P-gp inhibitors. Conformational changes of P-gp start at the nucleotide-binding domains once a substrate or inhibitor enters the different binding domains. Function of a membrane transporter depends on the energy from ATP hydrolysis. It is suggested that binding of ATP to the NBD and dimerization of the NBD is a driving force for this function. The thickness of the membrane and its other properties such as phospholipid and cholesterol content have crucial roles in the ATPase activity of P-gp. 
The presence of cholesterol is also essential for the activity of the P-gp pump. Molecular dynamic simulation analysis suggested that enhanced activity of P-gp for transporting substrates can be related to the cholesterol-rich domain of the membrane as accumulation of substrates occurs in this domain. Aromatic/hydrophobic interactions could be the key features in specification of the binding affinity for substrates/ modulators within the drug binding pocket of P-gp. Therefore, designing P-gp inhibitors that lack any interaction with CYP isoenzymes is an ideal perspective for future research.


1.Mollazadeh S, Sahebkar A, Hadizadeh F, Behravan J, Arabzadeh S. Life Sci. 2018;214:118–123. doi:10.1016/j.lfs.2018.10.048