Steven Mansoor, structural biology and drug development

Structural biologist Steven Mansoor, M.D., Ph.D., studies the structure and function of proteins — with a particular interest in ion channel receptors that play a role in the cardiovascular system. He is an assistant professor in the Department of Chemical Physiology & Biochemistry and the Knight Cardiovascular Institute, and a 2020 recipient of OHSU’s Faculty Excellence and Innovation award. We sat down to talk about his work.

What made you want to become a physician-scientist?

In a July 2022 review in Frontiers of Pharmacology, Mansoor, graduate student Adam C. Oken and the lab wrote about the therapeutic potential of P2XR receptors and why structural biology, using cryogenic electron microscopy, is ideally suited to facilitate structure-based drug design for P2XRs. Growing up, I always thought I wanted to be a physician. It wasn’t until I got to Reed college and started doing hands-on experiments that I became passionate about science. Then, during my junior year of college, I found out about the MD-PhD program, which bridges the gap between science and medicine. At that point, I knew I wanted to be a physician-scientist.

I am a medical doctor, not a surgeon. What do medical doctors do? We diagnose illnesses and treat patients with medicines. Throughout my clinical training, I always thought about how, for the overwhelming majority of medicines that we give to people, we have no idea how they work, especially at a molecular level. We know they interact with receptor A or receptor B for example, but we don’t know how. And because we don’t know how, these medicines oftentimes also interact with other off target receptors, thereby causing unwanted side effects.

The more I thought about that, the more I wanted to understand how these drugs bind to proteins. That would make it possible for us to be able to design them to be better, more specific, more efficient and to have fewer side effects.  Ultimately, trying to develop drugs that can really benefit my patients by limiting side effects — that’s what got me interested in structural biology and studying the shape and structure of ion channels.

What’s the focus of your research?

Using used cryo-electron microscopy, Mansoor and colleagues identified the inner workings of the P2X7 protein receptor. It is associated with inflammation, coronary artery disease, cancer, multiple sclerosis and more. (OHSU) Because Mansoor’s team solved the structure of the P2X7 receptor using Cryo-EM, Mansoor was invited to write a featured book chapter on the receptor’s structure. The book comes out in August.

We’re interested in targeted drug development. So we try to understand and study the structure of our protein targets in order to develop drugs that bind to them and control their function. For example, we may want a drug that activates the channel or a different drug that blocks activation of the channel. It depends on the physiological situation and the disease process at hand. And because these are prominent drug targets, the primary goal is the development of drugs that can treat certain conditions like high blood pressure, or prevent platelets from aggregating, or prevent people from getting atherosclerosis.

As a physician scientist, I have medical training — I’m a cardiologist — and then I have a doctorate in biochemistry. My work has the potential to be very translational —at the forefront of translating science at the bench to clinical research at the bedside.

My position at OHSU spans a basic science department — Chemical Physiology and Biochemistry — and a clinical department in cardiology — the Knight Cardiovascular Institute. Being able to have my foot in the basic research and clinical worlds is tremendously important for me, because when I need to discuss more clinical aspects of my research, I can access the Knight Cardiovascular Institute. And when I need to discuss the more basic science aspects of my research, I’m associated with the Chemical Physiology and Biochemistry department. So collaboration and being able to bridge discussions with basic scientists all the way up to clinicians is incredibly important.

OHSU, as an institution, has a uniquely collaborative environment. It’s very easy to walk into any department and ask a person for help, whether it’s a basic science department or a clinical department. That’s quite special.

What keeps you excited?

Since I was in graduate school, I’ve always been addicted to data — getting new data and analyzing new data. “There’s something thrilling about being the only person in the world that knows a particular result.” Granted 99.999% of the world doesn’t really care, but that doesn’t matter to me. Just seeing the data, interpreting it, thinking about what it means and how it might change the direction of the next experiment, it’s really exhilarating.

How is the Mansoor lab coming along?

I started my own independent lab in July of 2020, right in the middle of COVID. Since then, I’ve recruited the first graduate student that I’m mentoring. I’m looking forward to growth and new research.

“The Faculty Excellence and Innovation Award was incredibly useful to launching the lab. That award has really helped me kickstart things, especially since I started my lab right in the middle of COVID.” There was a potential freeze — where I wouldn’t have been able to hire anybody. But because I had foundation money, I was able to hire the graduate student as well as an additional three people. I could pay for anything and I did not need approval. This was all because I received the award made possible by the Silver Family Innovation Fund.

Moving forward, I’m really looking forward to nurturing and training the next batch of young scientists and seeing the interaction between my research and that of trainees —and where that takes my research. The mentor/mentee relationship is very dynamic.

What do you like about Portland?

I love Portland. I went to college in Portland; I did my M.D.-Ph.D. training at OHSU; I did my internship and residency at OHSU; I did my fellowship in cardiology and my postdoc at OHSU. Now I’m on faculty at OHSU. So I’ve been here for the duration of my career, and I don’t anticipate leaving anytime soon.

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