UT Health Science Center Researcher’s Experimental Work Integral to Nobel-Winning Protein Design

Dr. Seetharaman Jayaraman collaborated with Nobel Prize winner Dr. David Baker before joining UT Health Science Center in the Center for Cancer Research and the College of Medicine's Department of Pharmacology, Addiction Science, and Toxicology.

When Seetharaman Jayaraman, PhD, associate professor in the University of Tennessee Health Science Center College of Medicine, learned that his former collaborator and renowned computational biologist, David Baker, PhD, had won the 2024 Nobel Prize in Chemistry, he felt a deep sense of pride.

As a structural biologist, Dr. Jayaraman played a key role to validate some of Dr. Baker's groundbreaking theoretical ideas about protein design, which contributed to Dr. Baker's Nobel-winning achievements.

Dr. Jayaraman joined the UTHSC Center for Cancer Research and the Department of Pharmacology, Addiction Science, and Toxicology in 2023 after nearly five years at St. Jude Children's Research Hospital, bringing decades of expertise in protein structure, a specialized branch of biophysics.

"What we do as structural biologists is study the three-dimensional structure of protein molecules to understand their function," he said. Proteins, composed of diversely folded amino acid chains, serve essential roles in all living organisms. The function of each protein depends on its precise structure, just as the purpose of a hammer or a saw depends on how it's shaped, Dr. Jayaraman said.

Dr. Jayaraman's career in structural biology began with his PhD in India, followed by work in Canada and nearly two decades at Brookhaven National Laboratory in New York, one of only a few institutions in the U.S. capable of conducting large-scale, high-throughput protein determination experiments. It was at Brookhaven that Dr. Jayaraman first collaborated with Dr. Baker, who is now a professor at the University of Washington School of Medicine and an investigator at Howard Hughes Medical Institute. As collaborators, Dr. Jayaraman provided experimental validation for some of Dr. Baker's computationally designed proteins.

"We know that each protein's structure is unique to do a function, but Dr. Baker wants to do it the other way - to design a protein according to the function you want it to do," he said. "For example, if you want to remove toxins from the body, can you design a protein that can go in and remove the toxin from the body? Can you design a protein that can go in and suppress cancer growth? So, as part of the experimental team, I solved the protein structures to show that his computational design was correct."

Neil Hayes, MD, director of the UTHSC Center for Cancer Research, emphasized the importance of this teamwork. "Behind almost all major scientific advances is a team of the highest caliber. In the case of Dr. Baker's recent Nobel Prize, that team included at least one named scientist currently supporting the UTHSC Center for Cancer Research," he said. "The skilled experimental validation executed by our UT Health Science Center scientist Dr. Seetharaman Jayaraman is what gives confidence to Dr. Baker's theoretical work."

Dr. Baker's innovative approach to protein design has far-reaching implications, including potential treatments for diseases like cancer, in which proteins with altered structures drive tumor growth.

Throughout their time as collaborators, Dr. Jayaraman and Dr. Baker published seven research papers together on topics including design of a protein-based enzyme inhibitor, enone-binding proteins, catalytic dyads and oxyanion holes for ester hydrolysis, unnatural amino acid-dependent metalloprotein, optimization strategies for retroaldolase design, serine-containing catalytic triads, and repeat protein design. The success of these research projects underscores the impact of their combined work. "When I heard (Dr. Baker) won the Nobel Prize, I was thrilled to know I'd contributed to part of that accomplishment," Dr. Jayaraman said.

At UT Health Science Center, Dr. Jayaraman contributes to over a dozen research projects by assisting with protein structural studies as well as validating and improving pharmacological compounds to target specific proteins in cells. His contributions complement the efforts of a multidisciplinary team, with Dr. Jayaraman optimizing drug candidates through computational and structural biology.

"I do structural biology, and they do biology/pharmacology, and then we work together to understand the protein structure-function relationship and how it works in the cell, he said. "I consider myself fortunate to be a member of this team because my expertise differs significantly from that of the other faculty members, thus we complement each other. That's what's very important, and it's why we hopefully get some good results."

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