Structural savant is imaging proteins that clump to better understand diseases such as Alzheimer’s

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Professor Jose Rodriguez, a biochemist, was recently named one of C&EN’s Talented Twelve.

Jose Rodriguez picked up structural biology first as a hobby. In his free time while working on a Ph.D. in molecular biology at the University of California, Los Angeles, he collaborated with a physics professor on a problem critical to how biologists process X-ray crystallography data.

Now, as a professor at UCLA, Rodriguez is using a relatively new structural biology technique to investigate proteins that clump together. These aggregating proteins are associated with diseases such as Alzheimer’s, and the UCLA scientist hopes that understanding their atomic-level details will pave the way to treatments.

“In cancer and metabolic diseases, there is a long, successful history of using structural information to design inhibitors that eventually become drugs,” says David Eisenberg of UCLA, who was Rodriguez’s postdoctoral adviser and is a current collaborator. But with these aggregating protein diseases, “there have been few structures so far, and that is the frontier that Jose has been pressing out.”

The technique Rodriguez uses is microelectron diffraction, or microED. In X-ray crystallography, scientists shine a beam of photons on a protein crystal, and its atoms scatter the photons in a characteristic way that can be analyzed to determine its structure. But conventional X-ray crystallography has trouble with crystals made from clumped proteins—they’re too small to produce meaningful data. MicroED, meanwhile, can yield high-resolution data from these crystals because it uses a beam of electrons that interacts more strongly with a crystal’s atoms than photons do.

In 2015, as a postdoc in Eisenberg’s lab, Rodriguez published the microED structure of α-synuclein, a protein that produces ropelike fibrils in the brains of people with Parkinson’s disease. It was the first structure of a protein obtained by microED that hadn’t been solved previously by another technique.

As an independent researcher, Rodriguez is studying prions, the infectious proteins responsible for diseases such as bovine spongiform encephalopathy, also known as mad cow disease. He hopes his structural insights could help explain prion mysteries such as how healthy proteins get converted into infectious ones that aggregate.

Rodriguez is also working to make microED accessible to a wide range of researchers. “It’s fine if I can do it,” he says, “but how do you make it easier to use so everyone can be a structural biologist?”

Source of article: C&EN