A research team at the Scripps Research Institute has obtained the first glimpse of a protein that keeps certain substances, including many drugs, out of cells. The protein, called P-glycoprotein or P-gp for short, is one of the main reasons cancer cells are resistant to chemotherapy drugs. Understanding its structure may help scientists design more effective drugs.
The new research was described in the March 27, 2009, issue of the journal Science.
"This structure is an important advance and we hope it is just the beginning of more breakthroughs for us," says the study's senior author Geoffrey Chang, an associate professor at Scripps Research. "The structure is a nice tool for understanding how drugs are transported out of cells by P-gp and for designing drugs to evade P-gp preventing drug resistance. It's very exciting."
P-gp, a protein first identified in 1976, sits in the membrane that surrounds human cells, including those in the gut, intestine, kidney, and brain, where it functions as a gate keeper, shooing out potentially harmful agents. Problematically, P-gp not only transports substances that are harmful out of the cell, but also drugs targeted to cancer cells and HIV-infected cells, as well as some therapeutics aimed at alleviating psychiatric conditions.
"We've long known that P-glycoprotein plays a key role in multidrug resistance in cancer patients, and this work helps us understand how the protein can act on such a wide range of compounds," said Jean Chin, Ph.D., of the National Institutes of Health's (NIH) National Institute of General Medical Sciences (NIGMS), which partially supported the work. "In the future, scientists may be able to use these crystal structures to design chemicals that block P-glycoprotein's activity and restore sensitivity to chemotherapeutic agents."
Solving the Structure
The team, which included scientists from Texas Tech University Health Sciences Cente
|Contact: Keith McKeown|
Scripps Research Institute