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Last year he also became a principal investigator of a powerful new beam line, a research facility using an intense x-ray beam, now being built at the Stanford Synchrotron Radiation Laboratory. This beam line is specifically designed to help researchers solve the structures of large molecules.
HHMI: WHAT MAJOR QUESTION IS DRIVING YOUR RESEARCH TODAY?
DR: We’re trying to understand how ATP [a molecule that stores energy inside cells] and other large molecules are used to power the body’s machinery, which is a problem I started studying as a postdoc with James B. Howard at Minnesota. We’re beginning to learn how certain proteins, known as ABC transporters [for ATP binding cassette], manage to pump nutrients into living cells. These proteins use energy to accumulate molecules in cells, without letting any of the molecules leak back across the cell membrane.
X-ray crystallography has been very useful in figuring out how that’s done. If you want to understand how any system works—whether it’s a power plant, computer, or molecule—you have to know what it looks like. When we started, no structure of an ABC transporter had been determined, so we needed to fill the gap. We surveyed a number of different ABC transporters from different organisms before finding one—the protein that imports vitamin B12 into Escherichia coli bacteria—that would be appropriate for our structural studies. After producing suitable crystals of this transporter, we were able to determine its structure in atomic detail. Based on this analysis, we proposed that the transporter can pump molecules across a membrane by functioning like an airlock, where the energy provided by ATP is used to open and close the airlock doors in the correct sequence. This result, of course, helps us understand how transporters work in human cells.
Another thing that transporters do, unfortunately, is help cancer cells develop resistance to certain drugs. When these drugs enter the cancer cell, transporters may pump them out—just like bailing water out of a sinking ship—and prevent them from killing the cell. Ultimately, we’d like to know how transporters work in sufficient molecular detail to be able to stop this process.
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