Just How and Where Does P-glycoprotein Bind All Those Drugs?

Abstract

P-glycoprotein (P-gp) was one of the first discovered, and most highly investigated, multidrug efflux pumps. P-gp was discovered in drug-resistant cancer cells and its ability to mediate adenosine triphosphate (ATP)-dependent efflux of drugs can confer resistance to cancer cells. The protein contains two sites for the binding and hydrolysis of ATP to power the active transport process. Drugs are known to bind within the transmembrane domain that comprises 12 membrane spanning α-helices. Biochemical, pharmacological and biophysical investigations continue to strive towards generating a molecular mechanism for drug transport. In addition, X-ray structures are available for the mouse and Caenorhabditis elegans isoforms at resolutions of 3–4 Å. However, one of the central issues related to the transport process remains elusive. A detailed understanding of how the protein is capable of binding its astonishing variety and number of compounds, remains unsolved. The hydrophobic vacuum cleaner and drug flippase models have been generated to describe this enigmatic property and some of their proposals remain intact. The majority of data supports the presence of a large binding domain that contains individual sites for drug interaction. These interaction sites are linked by an intricate allosteric network and binding to the sites is in close communication with the ATP hydrolytic machinery. This review provides a detailed account of our current understanding of how one membrane transporter is able to bind over 300 compounds.