Kalodimos in the University's Structural Biology Nuclear Magnetic Resonance Facility.
Discovering a cancer mechanism is like solving a three-dimensional puzzle made of moving parts. Often, a research team might have a good idea of which key molecules are involved, but no clear picture of how those pieces work together. In a new paper published in Nature Chemical Biology, Charalampos Babis Kalodimos, a new faculty member in the department of Biochemistry, Molecular Biology, and Biophysics, identified a solution to a long-standing riddle — how does the drug cyclosporine help cancer patients?
Cyclosporine is an immune system suppressant, typically prescribed to prevent rejection of organ transplants. Over time, however, an intriguing trend was documented in dozens of papers. Patients who took the drug for non-cancer related reasons happened to experience better outcomes following cancer treatments ... but for decades, nobody knew why.
For any given question, there are often numerous techniques that might yield an answer. A typical lab asks a few questions about a particular biological system and tries out techniques that seem promising. Babis’ lab, on the other hand, asks a broad variety of questions on topics ranging from cancer to membrane proteins to bacterial systems to molecular chaperones. The unifying thread? Nuclear Magnetic Resonance (NMR) spectroscopy.
“The beauty of NMR is not only that you get high-resolution molecular structures, but also that you can see how they change over time, exactly where molecules bind, and where they are flexible,” says Babis, who depends on massive — and extremely expensive, therefore rare — high field instruments to produce exquisite visualizations of biomolecules. As Babis explains, the University of Minnesota has one of the best NMR centers in the country.
Imagine a video reel depicting a soccer play, where several players interact in order to eventually kick the ball past the goalie. If you only capture the final frame, you see a ball in a net, but you miss all of the information about how it got there. “You need as many snapshots as possible,” says Babis. “The intermediates, which are by far the most important, are the ones that reveal all the details about how things really happen.”
High field NMR machines use super-sized magnetic fields to generate thousands of crisp “snapshots” of molecular interactions in process, providing Babis with just the sort of intermediate images he needed to solve the case of cyclosporine.
What happens is that cyclosporine binds to an important protein called Cyclophilin A at just the right spot, preventing it from triggering a signaling cascade for cellular migration and invasion — the underlying causes of metastasis in cancer. It’s a simple and elegant mechanism, but one that was hard to see without some heavy duty NMR.
“What drives our research and our passion for research is the curiosity of finding out the fundamental mechanisms of how various molecular processes work,” says Babis, who is eager for his next big challenge — which is already in the works.
“Until recently, there were no structures of molecular chaperones in complexes with unfolded proteins,” says Babis, who last year became the first to document and publish one such structure. “We hope that within the next few years, we will have determined the structures of most of the chaperones out there. We believe this will be a major breakthrough that could utterly reshape our understanding of the field.”
“The beauty of NMR is not only that you get high-resolution molecular structures, but also that you can see how they change over time, exactly where molecules bind, and where they are flexible.”