Introducing Martin Gustavsson

What are the big research questions you are working on?

The really big question that we are interested is, is to understand how GPCR structure and dynamics control function. If we can understand that, we can use that to understand how GPCR’s work physiologically and to better target GPCRs as drug targets. Because even though GPCRs are an important drug-target, even though we have so many structures, there are still so many things we don’t understand. For example, you can have one ligand binding that fits one pattern of signaling and then you can have a different ligand that gives a whole different pattern. GPCRs exist in all these different conformations and how they move between these different conformations is really relevant to how they function. So that’s a fascination for me.

You are interested in both structure and function?

Absolutely. I did my postdoc at University of California San Diego. The goal there was to determine one structure. In the end, when I left, we actually didn’t have the structure. We do now and it will be published soon but that will be 8 years after we started. During this time, I got all these ideas about how we could learn about receptor function in other ways than just studying the structure and this has become a really big focus for me.

In my group, it is important to me that we are not dependent on a collaborator but can actually do the function experiments ourselves. We can try many more things when we have control of it ourselves. For example, if we see that a mutation has a favorable effect on the stability of a target for structure determination, we can right away test if the mutation is also affecting protein function in human cells. If the mutation can tell us something about receptor function, we can characterize it further and potentially publish even if ends up being a dead end for structure determination.

One example of this was when I, as a postdoc, tested truncated receptor constructs for crystallization. I noticed some interesting things about how the truncated constructs bound to ligands and with some binding and signaling experiments, it turned into a nice publication even if the truncations were not the way to go for structure determination (Gustavsson M. et al., Sci Signal. 2019).  

How would you sum up your approach?

I have expertise in NMR and X-Ray Crystallography but my strong point is not necessarily a specific expertise with a method. My strong point is to understand how to make really good samples and how to get the most information out of those samples. That is how I want to see my group: we make the best possible samples we can and then we get the most information that we can using the technique that is best suited for that sample.

During my postdoc, I published a protocol for expression and purification of chemokine receptors. Like other GPCRs, chemokine receptors are difficult to produce, especially in complexes with their native protein ligands. The protocol I developed describes how complexes between chemokine receptors and their native chemokine ligands can be expressed and purified from Sf9 cells. I believe these methods will enable future structural and biophysical studies of chemokine receptors, which could catalyze the development of new therapies.

Can you tell us a bit more about your academic journey?

I am originally from Sweden and did my Masters in Sweden. But during my Masters, I went on exchange to the University of Minnesota. The group I was working with there studied membrane proteins using NMR and I decided I wanted to stay and so I did my PhD at the University of Minnesota.  

For my postdoc, I wanted to keep working with membrane proteins but I also wanted to branch out a little bit. In the group I was in, there was a lot of NMR, so it was basically one specific method. At the University of California San Diego, I did a postdoc where I kept working with membrane proteins but I started using X-Ray Crystallography. I also started doing a bunch of expression and purification in eukaryotic systems as well as mammalian cell-culture and pharmacology, like binding and signaling assays. It was a chance to learn new things while staying on a specific track.

And how did you end up working in Copenhagen?

It was sort of a coincidence. I ran into Mette Rosenkilde who is the leader of the section I am in now at a conference and she knew my postdoc supervisor. I started talking to her about the possibilities of coming here. After that I started applying for starting grants. I applied for the Sapere Aude, the Lundbeck Fellow, the Villum Foundation... A little time after I was making these applications, they had an open call for a Tenure Track Assistant Professor at BMI, so I applied for that. I think it helped that I already had contact with the Department because when I applied for all of these grants, I did it with recommendation letters from the Department showing that the Department supported me coming here to start a group. In the end, it was fantastic timing. I received both the Villum Young Investigator grant and the position at BMI.

It sounds like you have had a dream run. Do you have any career advice for young researchers?

When I started out as a PhD student, I was very focused on membrane proteins and NMR and I didn’t really question what I was doing. But then when you are a postdoc and starting your independent career, you realise that it matters what you focus on because you need to attract grants and you need to be able to bring in funding.  

It is important to think about what target you work on and make sure that it has practical applications. That is why I started working with GPCRs. It is quite obvious what the importance of GPCRs are and it is very easy to give this little speech about how they are the biggest class of drug targets.

I think it is also important not to get stuck in one method because the methods are developing so fast and they can go out of fashion. You really need to follow the development of the methods as they occur. This can be a challenge because when you are applying for a post-doc, they are looking for someone with experience. But there are ways around that. I could say that I had experience with membrane proteins and could bring that experience while learning X-Ray Crystallography.

Finally, it is really important to think about what different options you have, even if you want to study structure. You need to publish and if you put all your eggs in the determining the structure basket, then it is a big risk. It has taken 8 years for us to publish the structure I worked on during my postdoc. So I also work a lot with sample preparation and function. 

I think my experience also shows that it is really important that I was a good fit. I was super lucky. There are so many more people than there are positions and a lot of it was coincidence but my research really fits in at BMI. Because it was such a good fit, I was already in contact with the Department.  

How has the experience been of setting up your own lab?

The first five months I was alone and was focused on setting up my lab.  It helped a lot to have the Villum grant so I already had a plan of what I needed to do. It’s also been really important to have the support from my section leader, Mette Rosenkilde. Her lab is set up with a lot of the equipment that I need and if I didn’t have access to that I wouldn’t be able to do a lot of the experiments that we are doing integrating signaling and binding aspects. That has been super valuable. Now, my group has four members. These include Postdoc Ganna Krasnoselska, PhD student Stefanie Eberle and PhD student Fabian Pfersdorf. We have also been lucky to work with some people here who are Cryo-EM experts as I am now starting to work more and more with Cryo-EM.

Where can I learn more about your research?

To find out more about my protocol for producing chemokine receptors, see: Gustavsson M, Zheng Y, Handel TM. Production of Chemokine/Chemokine Receptor Complexes for Structural Biophysical Studies. Methods Enzymol. 2016; 570:233-60.

You can also read my latest publication here: Eberle SA, Gustavsson M. A Scintillation Proximity Assay for Real-Time Kinetic Analysis of Chemokine-Chemokine Receptor Interactions. Cells. 2022 Apr 13;11(8):1317.