Andrew Lee, PhD

Associate Professor

Division of Medicinal Chemistry and Natural Products

 

Research interest

Using NMR spectroscopy to study the relationship between protein structure and dynamics and how these respond to perturbations such as binding (natural ligands or drugs) and mutation (evolution).

When Andrew Lee finished his PhD at the University of California Berkeley in 1996, the native Californian decided it was time for a change of scenery.

He came to the East Coast to do his postdoctoral fellowship at the State University of New York at Buffalo, where the winter weather was a quick reminder that he was a long way from home.

"I went from Berkeley to Buffalo, and that was kind of an interesting change,” says Lee, now an associate professor at the UNC School of Pharmacy.

Lee’s stay on the East Coast warmed up as he moved south. His postdoctoral fellowship moved to the University of Pennsylvania, and after he finished in 2000, he joined the faculty at UNC Chapel Hill, where the temperature wasn’t the only thing he liked.

“There’re lots of great research programs going on on campus, and it’s still all on one campus physically, so it’s easy to interact with people here,” says Lee, who is in the School of Pharmacy's Division of Medicinal Chemistry and Natural Products and has a joint appointment in the School of Medicine's Department of Biochemistry and Biophysics.

“It’s a really good mix of high-level science and a pleasant atmosphere for doing science. Those two don’t always go together. When you have high-level science, sometimes it makes it so competitive that it’s unpleasant to be in that atmosphere. It’s more cooperative, more collaborative here.”

Fruits of Collaboration

That collaborative environment has been a big help for Lee’s research, which focuses on protein dynamics and how they relate to protein structure. When Lee needed a protein to use as a model system, he picked one that a fellow researcher was studying—eglin c—even though it might have seemed an unlikely choice at first glance.

“Eglin c is not a drug target. It’s not the sexiest protein in the world, as we say in science,” Lee says. “The eglin c is a protein from a leech. If you had something that could inhibit eglin c, it wouldn’t really affect our health very much, unless you found yourself in a pond with leeches all over you.”

However, the data collected from eglin c is fundamentally applicable because Lee is using it as a model system for proteins that are globular (folded), and most proteins fall into that category. Eglin c also had properties that Lee liked, such as its small size and high solubility. The biggest plus, however, was the fact that Marshall Edgell, a professor in UNC’s Department of Microbiology and Immunology, is also studying eglin c. Lee says the collaboration with Edgell has saved his lab “years and years” of work.

“What we’re doing is very complementary,” Lee says. “Marshall was going to have lots of thermodynamic data on coupling between different pairs of amino acids in this protein, and that data is not easy to come by. For us, it was too irresistible to stay away from that.”

Movers and Shakers

Proteins, which are long strings of amino acids, assume specific shapes to do specific jobs. For example, hemoglobin folds into a shape that carries oxygen. However, protein structures are not static.

“For years and years, people tried to understand proteins through their structures like they’re average, static structures, but now we know that proteins are not static,” Lee says  “They’re actually highly dynamic and are moving on timescales from very, very fast to fairly slow.”

Those structural changes in proteins could cause trouble for drug development. Proteins recognize and bind to compatible partners to form the basis of all biological processes. Drugs that target disease-causing organisms work the same way, identifying and locking on to receptor sites of specific proteins in an organism. However, when the proteins making up the receptor sites change, the drugs that target those sites can no longer lock on to them and thus become ineffective.

Atoms in a protein can communicate with each other—even if they are not touching—and cause a reaction or movement. Lee is studying how this communication occurs.

“These are basically molecular machines, and like any machine, these things have moving parts,” Lee says. “To understand how an engine works or how a machine works, you need to understand what’s moving, why does it move, how does it move, things like that. We’re interested in trying to locate where motion is. That’s something that’s not obvious to more traditional structural biology.”

Funding and Equipment

In 2004, Lee received nearly $2.3 million in funding for his research. The National Institutes of Health gave him nearly $1.4 million to support his work with eglin c. Lee also got a $900,000 grant from the National Science Foundation for the protein-recognition component of his study, which looks at a PDZ domain in the human protein hPTP1E. A PDZ domain is an area of a protein that recognizes other proteins.

The primary tool Lee uses in his research is NMR spectroscopy. He says it is helpful that the School of Pharmacy has its own NMR facility—which he oversees—because the equipment is on site and can be customized to the specific needs of his experiments.

NMR spectroscopy, Lee says, allows researchers to essentially “see” individual atoms. It is also a powerful technique because it offers a wide array of experiments.

“There are hundreds, perhaps thousands of pulse sequences you can run on the spectroscopy as opposed to other techniques, where there’re only two or three varieties of experiments,” Lee says. “This field is still developing, too, and people are still inventing new experiments to run on NMR machines.”

In addition, Lee says NMR spectroscopy is the only technique with atomic resolution that allows the study of macromolecules in solution, enabling researchers to observe proteins in their natural state.

“Proteins in your cells are in water because there’s a lot of water in your cells,” Lee says. “These other techniques tend to remove water and can form crystal solid lattices. In NMR, you’re actually monitoring these molecules in their natural state, an aqueous state. And it’s the only technique that can do that with atomic resolution. So it’s fairly unique. On top of that, it’s really the best experimental technique for studying motion.”