A Cell's Vacuum Cleaner | March 30, 2009 Issue - Vol. 87 Issue 13 | Chemical & Engineering News
Volume 87 Issue 13 | p. 10 | News of The Week
Issue Date: March 30, 2009

A Cell's Vacuum Cleaner

Researchers solve the structure of P-glycoprotein, which kicks molecules out of cells
Department: Science & Technology
The first crystal structure of a mammalian P-glycoprotein.
Credit: Science © 2009
The first crystal structure of a mammalian P-glycoprotein.
Credit: Science © 2009

WHEN CANCERS STOP responding to chemotherapy, one of the culprits is a protein transporter that expels drugs out of diseased cells, thereby preventing the benefits of treatment. Now researchers are reporting the first mammalian X-ray crystal structure of this transporter, P-glycoprotein. The work provides a first step toward the design of drugs to thwart its action.

Human P-glycoprotein is often referred to as a "hydrophobic vacuum cleaner" because the membrane protein sucks up all sorts of greasy molecules—including beneficial drugs—that make their way across the lipid bilayer and sends them back outside the cell, notes Geoffrey Chang of Scripps Research Institute. He led the team of researchers that solved the structure of mouse P-glycoprotein to 3.8-Å resolution (Science 2009, 323, 1718).

Yet the pump can also do good—for example, by sitting on the placental membrane, where it protects a growing fetus from toxic chemicals. In fact, the enzyme's dual role as both an essential shield and overprotective barricade is exemplified in the blood-brain barrier, where P-glycoprotein protects the brain from harmful chemicals in blood while also frustrating drug developers by kicking out possibly useful treatments for deadly brain diseases.

"This is very exciting work," comments Stephan Wilkens, a biochemist at Upstate Medical University, in Syracuse, N.Y., who studies P-glycoprotein by electron microscopy. "Many laboratories and drug companies have been working for years on getting such a structure."

Although the structure "is a great start" for drug developers wishing to selectively block the pump, Wilkens adds, "the resolution of the side chains isn't quite good enough to do structure-based drug design yet."

Chang's team found that the enzyme's substrate-binding pocket is a large internal cavity, open to both the membrane and the inside of a cell, and that it is full of aromatic and hydrophobic amino acids. When they solved the structure in the presence of two stereoisomers of a greasy inhibitor, they found that the isomers bound in different parts of the binding cavity, showing just how promiscuous the protein transporter is.

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