(Josh De Luca)
When Saket Bagde made an early attempt in 2017 to use the Stanford Synchrotron Radiation Lightsource at the Department of Energy’s SLAC National Accelerator Laboratory to determine the structure of a particularly tricky protein, SLAC scientist Irimpan Mathews was skeptical Bagde could do it. “I thought this poor student is not going to get any results,” Mathews said.
But as Mathews soon learned, Bagde is an exceptionally motivated scientist with a strong will to answer the toughest questions. His unwavering determination led Bagde to achieve a feat scientists had been trying to accomplish for more than 30 years: accurately visualizing the entire structure of a protein complex called polyketide synthase, a molecule used in the production of antibiotics and other drugs. For his efforts, Bagde has been awarded SSRL’s 2022 Spicer Young Investigator Award.
“I’m very excited to receive this award,” says Bagde, a graduate student in Cornell University's Department of Molecular Biology and Genetics. “Recognitions like this remind me to take a pause and appreciate all the amazing people I’ve worked with. Together, our skills have led to the development of something that is going to help people.”
Visualizing protein blueprints
Polyketide synthase (PKS) is a type of enzyme that helps perform chemical reactions to produce important antibiotics, such as erythromycin and lasalocid. “We call it nature's molecular assembly line, because polyketide synthase works like a manufacturing assembly line,” Bagde explained.
Similar to a manufacturing assembly line, there are several different machines, or modules, within PKS that are responsible for building separate parts of the final product. If scientists could make small programming changes in individual modules within PKS, it could mean the assembly line would naturally produce a new, custom product – for instance, a potentially more powerful antibiotic.
But in order to make tweaks to the molecular machinery, scientists must first figure out how modules are built and work with one another. “For the last 30 years, no one has been able to answer this question,” Bagde said.
Driven by the excitement of a novel project and a bit of naive optimism, he says, Bagde and his colleagues drew on the high-resolution X-ray crystallography capabilities of SSRL to determine the structures and components of this important protein system. Now, Bagde is the first author of a paper describing the results of this work, which was published in Science last fall.
Among his several other publications, Bagde is also a co-author of papers in Nature and Science and the first author of a study published in Science Advances earlier this year. The study describes aspects of the activation of a GTPase, a “molecular switch” important for several cellular processes.
An example for others
In letters nominating Bagde for the awards, several researchers noted Bagde’s strong commitment to helping others and his successful mentorship of many undergraduate students.
Bagde says he is grateful for the enthusiastic, steadfast support of his mentors at the University of Texas El Paso, Cornell University, and SLAC. As a gay, South Asian man from the marginalized Dalit community, he’s also proud to represent those communities in science, he says. “I hope I can be an inspiration to others who will bring their diverse backgrounds to academia and see that people with different backgrounds can achieve scientific accomplishments and receive these awards.”
The Spicer Award will be presented to Bagde during the 2022 SSRL/LCLS Annual Users' Meeting and Workshops at SLAC, which will be held September 26–30. The award is named in honor of the late William Spicer, who co-founded what would become SSRL, and his wife Diane.
SSRL is a DOE Office of Science user facility. The SSRL Structural Molecular Biology program is supported by the DOE Office of Science and the NIH National Institute of General Medical Sciences.
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