Illuminating the hidden world of membrane proteins

Dr Jason Schnell joined the Department at the beginning of May as a group leader. He did his PhD at the Scripps Research Institute in San Diego and then spent nearly 5 years as a postdoc at Harvard Medical School in Boston in the lab of Dr James Chou. There he worked on proteins embedded in cell membranes including a group known as ion channels which act as pores and allow ions to pass through the membrane. In 2008, they solved the structure of the first viral ion channel at high resolution using NMR1 [Nuclear Magnetic Resonance].

Jason in front of the 950 MHz NMR spectrometer in Oxford

Jason in front of the 950 MHz NMR spectrometer in Oxford

Here Jason talks to Jane Itzhaki about the move to Oxford and his research

Jane Itzhaki: Why did you choose Oxford Biochemistry?

Jason Schnell: On the one hand I'm driven by my research, and Oxford has a long history of doing great research. It's particularly good to be here because the department is both strong and large. That's very unusual. The sort of work I do is on an atomic level and you never know which direction your research is going to go. But I know that no matter what direction it goes, there will be an expert here. That's incredibly important.

You also can't over-estimate how important the new building is. Its design provides many opportunities for spontaneous interaction. That can be valuable because scientists, by nature, focus tightly in on problems, but sometimes the solutions to those problems come from unexpected places. So we have to work particularly hard to make sure we interact with people who are doing different kinds of work.

The second part is the teaching. I think that's a very rewarding and important part of anyone's research career. I'll be teaching and tutoring. Here you have the tutorial system which I think is truly unique in allowing a dialogue with students, so I'm very excited to be doing that.

Diagram showing the M2 channel from the flu virus. The channel is sitting in the viral membrane, and the inside of the virus is at the bottom of the figure

Diagram showing the M2 channel from the flu virus. The channel is sitting in the viral membrane, and the inside of the virus is at the bottom of the figure

JI: What were you researching at Harvard?

JS: I worked in the lab of James Chou on a membrane protein that's found in the influenza virus. It's an ion channel called M2. It sits in the viral envelope and allows protons to pass through the envelope. This is a critical step in the viral life cycle. It's a relatively small protein and also the target of a class of anti-viral flu drugs called the adamantanes. Unfortunately, nearly all the flu viruses now circulating are resistant to this class of drugs - it's basically useless at this point. The idea is to understand how this drug interacts with the M2 ion channel in the drug-sensitive type2, so that we figure out if there is some way to get around this drug resistance and make a new generation of drugs that is effective against current strains

JI: What did you do to find out how the drug and ion channel interact?

JS: This drug-protein interaction had been known for about 25 years. But membrane proteins such as M2 are incredibly difficult to look at at high resolution [using the preferred method of x-ray crystallography]. They're tricky things to work with because they behave like oil droplets and stick to each other. So a significant bottleneck is getting crystals. With something like M2, we thought it may be easier to look at it in solution using NMR where you don't need to form crystals. Solution-state NMR does suffer from size limitations - it can't look at very large proteins - but M2 seemed like a good test case for using NMR to get the high resolution structure.

It turned out to be just that. We determined the structure of the M2 protein and drug together and did follow-up studies to establish how the resistance occurs. Unfortunately, it doesn't look like it's going to be very easy to design a second generation of antiviral drugs that target the same site as these drugs do. One avenue of research that I'm looking into now is investigating other parts of the protein. We looked at only the channel portion and it may be that there are other parts of the protein with essential functions that could be targeted.

JI: What research will you be doing here in the department?

JS: It turns out that the class of drugs that is now useless to fight the flu virus is also used to alleviate the symptoms of neurodegenerative diseases such as Alzheimer's and Parkinson's. The drug used for these diseases is called memantine. This class of drugs interacts with many different ion channels. So in fact these drugs are still useful, not for fighting the flu but for other purposes.

The target of the drug [in neurodegenerative diseases] is an ion channel called the NMDA [N-methyl-d-aspartate] receptor ion channel. The mechanism is quite complicated since the drug seems to have two distinct binding sites on the NMDA receptor. What I hope to do is understand which parts of the protein the drug interacts with. Once you have some information about what the drug-protein interaction looks like, there's the hope that you can design second generation drugs - something that's better and more specific, with less side-effects.

JI: What are the broader aims of your research?

JS: In fact, there are many small molecules3 that modulate ion channels, but there's very little atomic-level information about how this occurs. NMR is very good at rapidly looking at these kinds of interactions, but this has been mostly applied to non-membrane proteins. So a broader vision that I have for my research is to bring this approach into the membrane protein field. Membrane proteins are one of the most important therapeutic targets because they connect the cellular interior to the outside world. Turning on or off one of these proteins can lead to very big cellular changes, which is one reason why they've become important drug targets. Bringing a new tool to this field is exciting because it's like shining a light into a dark corner.

JI: What is Oxford like to do this type of work?

JS: This is one of the best places in the world to do NMR. The NMR facility is one of the largest in the world. Not only is there an ultra high-field NMR machine, which is important for high sensitivity, but there's also a wide range of available fields, which increases the numbers and types of systems we can look at.

JI: Will you be working with particular colleagues in the department?

JS: I'll be working closely with several people inside and out of the department, including virologists such as Nicole Zitzmann who works on viral ion channels, and Phil Biggin who's a computational biochemist interested in NMDA receptors among other topics. I suspect there'll be many future collaborations with the computational biochemists because their work nicely complements the results we can obtain from NMR. For example, we can precisely describe the parts of an ion channel that are flexible and change structure, but we can't necessarily describe what exactly those motions look like. Computational studies can fill in that information.

JI: What are your interests outside work?

JS: Since I'm new to Oxford, my favourite pastimes recently have been hiking and exploring. One of the things that was key in the end to deciding to come here is that Oxford is a really special city. You have a very dense, vibrant urban centre surrounded by beautiful countryside. I happen to live on the edge of town, which is only 10 minutes walk from the centre. But I'm also only a 2 minute walk from the Thames path and Port Meadow.

  1. Schnell, J.R. and Chou, J.J. Structure and mechanism of the M2 proton channel of influenza A virus. Nature 451, 591-5 (2008).
  2. 'Drug-sensitive type': the original non-mutated form of the M2 channel that the adamantane drugs inhibited.
  3. 'Small molecules': molecules that interact with, and affect the function of, target proteins. These small molecules have the potential to be developed into drugs against those proteins.





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