La Jolla, CA, September 7, 2001 -- A scientist at the Scripps Research Institute (TSRI) has published an x-ray crystal structure on the cover of the current issue of the journal Science that provides the first detailed glimpse of a membrane transporter protein, a finding that could be useful for improving cancer therapy and fighting antibiotic-resistant bacteria.
Antibiotic-resistant bacteria are a major problem in public health in the United States and worldwide. The World Health Organization estimates up to 60 percent of all hospital-acquired infections worldwide are caused by antibiotic-resistant bacteria and that the total cost of treating them is approximately $10 billion a year.
One of the ways that bacteria resist antibiotic drugs is by using membrane transporters—large proteins that sit in the cell membrane and move other molecules in and out. In human cells, one of the important roles these transporters play is removing harmful toxins.
Unfortunately, harmful bacteria use transporters to nullify antibiotics. And certain cancer cells do the same thing, expressing membrane transporters on their surfaces that undermine the potency of chemotherapy drugs.
"We actually have very good drugs to fight cancer and to kill bacteria," says Assistant Professor Geoffrey Chang, Ph.D., of the Department of Molecular Biology. "[But] they can't always get in the cells to work."
According to Peter E. Wright, Ph.D., Chairman, Department of Molecular Biology at TSRI, "Chang's structure for the protein MsbA from the bacterium E. coli is a breakthrough, opening the door for scientists to design a new class of drugs that patients would take in conjunction with antibiotic or chemotherapeutic agents to keep those drugs in the cells and increase their efficacy."
MsbA transports lipid A, a component of bacterial cell walls, from the inner to the outer membrane of bacteria and is necessary for bacterial cell growth. It belongs to the ATP Binding Cassette (ABC) transporter molecule family. ABC transporters are ubiquitous on the cell surfaces of almost all organisms.
"This is one of the largest superfamilies of transporter molecules," says Chang. "They transfer drugs, sugars, peptides, and all sorts of things in all organisms from bacteria to [humans]."
"This [work] could shed light on antibiotics, but because of the similarities to human pumps, it could be relevant for human chemotherapy as well," he says.
The structure of MsbA is a dimer with two identical subunits. These subunits stretch across the cell membrane, coming together at the top (outside of the cell) and opening up like two outstretched arms on the inside of the cell. When the arms encounter lipid A, they close around the polar molecule, flip it over, and send it through the top to the other side of the membrane.
Membrane protein structures have been notoriously difficult to solve because they do not form good crystals, an important first step in solving a structure. But by working with many different protein preparations and testing thousands of different buffer conditions, Chang was able surmount this problem.
The research article, "Structure of MsbA from Escherichia coli: A Homolog of the Multidrug Resistant ATP Binding Cassette (ABC) Transporters" is authored by Geoffrey Chang and Christopher B. Roth and appears in the September 7, 2001 issue of the journal Science.
The research was funded in part by the National Institutes of Health.
The above post is reprinted from materials provided by Scripps Research Institute. Note: Materials may be edited for content and length.
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