Sandbox PgpWWC

P-glycoprotein (P-gp, ABCB1) is an ATP binding casette (ABC) transporter that hydrolyses ATP for conformational changes after a variety of substrates are transported. It is one of the membrane proteins responsible for the multi drug resistance (MDR) in cancer treatment, as well as various other drug therapies.^[1][2] ABCB1 can be found in tumor cells, as well as in the liver, kidney, adrenal gland, intestine, blood-brain barrier (BBB), placenta, blood-testis barrier, and blood-ovarian barriers. An effective MDR transport protein, the high amount of active ABCB1 substrates stems from the polyspecificity for hydrophobic and aromatic compounds.^[3]

Hydrophobic, Polar

Gottesman, M. M., Pastan, I., & Ambudkar, S. V. (1996). P-glycoprotein and multidrug resistance. Current opinion in genetics & development, 6(5), 610-617.

History

Structure

ABCB1 is located in the cellular membrane, adopting an inward-facing "V-shaped" structure. Since the hydrophobic substrates are hydrophobic and can partition into the lipid bilayer, research suggests that substrate enters ABCB1 through two portals within the lipid bilayer.^[1] When a substrate binds to the binding site, a conformational change causes the protein to open to the outside of the cell, releasing the substrate. ATP is then hydrolyzed to re-induce the inward-facing conformation in preparation for the binding of another substrate compound from the bilayer.^[4] This efflux of substrate out of the cell prevents the accumulation of potentially toxic xenobiotics; however, this effective expulsion of a wide variety of substrates causes the multi-drug resistance.

The polyspecificity of ABCB1 is often attributed to a large internal cavity of ~6,000 Å that can transport up to two compounds simultaneously ranging from sizes of 330-4,000 Da. Three binding sites have been proposed, including the H (Hoescht), R (rhodamine), and P (prazosin and progesterone) sites. Since multiple substrates can be transported simultaneously, the binding of substrate to one site can stimulate the transport in the other sites. For example, the substrate binding on the P site stimulates transport at the R and H sites. However, these regions signify areas of residues that interact with substrates, while binding sites and the corresponding residue interactions are specific for different substrates transported. This specific affinity suggests primary and secondary sites that overlap.^[1]

Clinical Relevance

As mentioned previously, ABCB1 is located in the liver, kidney, adrenal gland, intestine, BBB, placenta, blood-testis barrier, and blood-ovarian barriers. Furthermore, ABCB1 is overexpressed in tumor cells. The presence of of ABCB1 in these locations prevents the entry of toxins into the cells, but also prevents the accumulation of therapeutic drugs. For the BBB, this protein prevents the entry of many psychotherapeutic drugs.