In this interview, Tim Cross, Director of the NMR and MRI programs at the National High Magnetic Field Lab (NHMFL) in Tallahassee, Florida, talks about his research into protein structures in viruses and bacteria, and how the findings will affect medical research into disease prevention.
Please give a brief introduction to the work your research group is doing.
My research group is focused on the structure and function of membrane proteins. We utilize Solid-State NMR spectroscopy as a way to look at these proteins in a native-like lipid bi-layer environment. It turns out that that’s actually critical. The structure of these proteins is dependent upon their environment.
So, we look at proteins from influenza, and from mycobacterium tuberculosis, focusing on characterizing drug targets and understanding how they function, so that maybe a better drug can be developed, to inhibit these diseases.
Can you share some results of your recent work?
One of the proteins from the influenza virus that we’ve been looking at is called the M2 proton channel. This is the channel that’s in the viral coat that allows protons to flow into the interior of the virus particle. And if you block it, you prevent infection, or you stall infection - so that’s a really exciting protein to be working on. We have discovered the mechanism by which protons are transported through this channel, and now we’re in the process of actually looking at new pharmaceuticals, to prevent the flow of those protons.
It turns out that couple of years ago, there was a mutation in this virus, during the swine flu pandemic; and so 2 of the 4 possible drugs that were available on the market are no longer effective, because of this mutation. So, there is a desperate need for new drugs.
I also work on a longer-range project on mycobacterium tuberculosis. 1.3 million people per year are killed by tuberculosis, and we don’t understand very much about how this bacterial cell divides. In order to work out how we could prevent division, we’re looking at the proteins that are involved in what’s known as the divisome - a cluster of proteins that are involved in cell division.
We have just recently characterized the three-dimensional structure of one of the key proteins that recruits the other proteins of the divisome to that site of cell division. And we’re looking now at a number of the other proteins that bind to this one first protein called CRGA, and hopefully we will be able to figure out how to disrupt the activity of these proteins as they come together in a cluster.
What impact could your work have on the biological and medical fields?
The impact is really going to be dependent upon how we can progress with this information. If we can collect more of these structures, learn more about how these membrane proteins actually function, then that’s going to be tremendously useful to the pharmaceutical industry, and for my own collaborators that take advantage of these structures to determine what molecules will bind and inhibit the function of these proteins.
It is those inhibitors, which then become good leads for pharmaceutical development. And that’s absolutely what’s needed in these days. If you see any of the news stories about how drug resistant tuberculosis is killing so many people, because of the side effects of these very toxic drugs that they are having to take at this time. So, we need more pharmaceuticals, better pharmaceuticals; and that is the long-term goal for the research.
What is the importance of instrumentation in your research?
The instrumentation is at the heart of it. Without superb instrumentation, without state of the art technology, this research goes nowhere. In the early 2000’s, we were routinely burning up membrane protein samples. We could look at peptides, which were relatively insensitive to temperature, but proteins were just too sensitive. Being able to get the electric fields out of the sample was an absolute revolution for us. And now it has really opened up this whole field of research.
What technological developments would help push your research forward?
Now we are looking for more sensitivity, we need higher magnetic fields in order to look at the interactions, in order to resolve the resonances, in order to solve larger molecular weight proteins structures. It’s really, really critical that we have access to this technology.
About Dr. Tim Cross
Dr. Timothy A. Cross is an American academic chemist who specializes in nuclear magnetic resonance (NMR) spectroscopy, membrane and computational biophysics, and biomathematics. He is a Professor of Chemistry at Florida State University and the Director of the NMR Program at the National High Magnetic Field Laboratory. His research focuses on the sets of proteins that are important for the pharmaceutical industry in the treatment of diseases such as tuberculosis and AIDS.