Cell membrane protein discovery uses NMR spectroscopy

Guelph, ON – University of Guelph physics professors Vladimir Ladizhansky and Leonid Brown say they have perfected ways to determine the structure of large proteins found in cell membranes throughout the body.

Their work may help drug companies and other researchers zero in on new drug targets and design better drugs for ailments ranging from heart disease to eye and kidney problems.

Their research appears in a new paper published online September 8 in Nature Methods.

The researchers demonstrated a new way of looking at structures of cell membrane proteins using solid-state nuclear magnetic resonance (NMR) spectroscopy. These complex molecules in membranes perform many important functions, including relaying signals, passing substances in and out of cells, and governing immune responses. They account for about 40 percent of all proteins in the body.

About half of all drugs target these proteins, said Brown. “Membrane proteins are primary drug targets for so many diseases.”

But out of almost 100,000 known protein structures, only about 400 membrane proteins have been mapped so far. These molecules are complex and hard to work with, said Ladizhansky.

Normally researchers use X-rays to look at protein structure. But that method often distorts the molecules through crystallization and doesn’t allow researchers to study them in their natural state.

Now the Guelph scientists have perfected a reliable solid-state NMR method to study molecules embedded in lipids, as they normally exist in membranes.

Knowing protein structure helps researchers understand how molecules work, Ladizhansky said. “The impact on drug design is huge. It’s hard to create new drugs without knowing structures.”

Drug companies now use high-throughput screening processes to plow through candidate molecules, he said. That’s complicated, time-consuming and costly. “If you know structures, you open the way for rational drug design.”

The Guelph researchers will use the technique to study medically relevant proteins.

Brown, a biophysicist, has looked at aquaporins that regulate movement of water in and out of cells throughout the body, from kidneys to eyes. “They are extremely important in fluid balance, and are associated with many diseases,” he said.

He and Ladizhansky also plan to study a membrane receptor protein that helps the body to bind caffeine and regulates blood vessels in the heart.