P-glycoprotein (P-gp, ABCB1) is an ATP binding casette 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. The entrance of substrate into the structure is argued to occur from a cavity in the lipid bilayer.[1] When a substrate binds to the binding site, a conformational change causes a scissor-like action that 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 caused 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 the P (prazosin and progesterone) sites.[1]
Clinical Relevance
