How does P-glycoprotein bind so many drugs?

Callaghan R

Division of Biomedical Science & Biochemistry, Research School of Biology & Medical School, Australian National University, Canberra 0200, ACT.

P-glycoprotein (P-gp) gained notoriety for its role in conferring drug resistance to an astonishing number of cytotoxic drugs used in oncology. The protein is able to confer resistance by preventing sufficient accumulation of chemotherapy drugs within cancer cells. P-gp is one of three multidrug efflux pumps in humans and their actions have been the focus of considerable research. Recently, an x-ray crystallography based structure has been presented for P-gp and has been touted as the "missing piece in the puzzle" to generate a mechanistic understanding of this protein. Has this been achieved yet and is there any benefit to further biochemical studies on P-gp? Our continuing research focus is to provide a dynamic understanding of the drug translocation process of P-gp. In particular, we aim to locate the drug binding site(s) on the protein and describe their communication with the energy providing domains. This information will be used to describe the precise steps involved in multidrug transport at a molecular level.