Scientists discover the structure of virus-fighting protein

Yale researchers have made a breakthrough in understanding a protein that maylead to new drug treatments for diseases likeviral infections and cancer.

A team of Yale scientists decoded the molecular structure of RIG-I, a virus-fighting protein, this Januaryand published their research in this month’s issue of Cell on Oct. 13. Researchers on the team said the discovery has the potential to lead tonew treatments for life-threatening viruses.

“Knowing RIG-I’s anatomy gives us the opportunity for structure-based drug design,” said Anna Pyle, a professor of molecular biochemistry and biophysics, referring to drugs designed to target specific proteins.

Dahal Luo, a postdoctoral scientist in Pyle’s lab, said that RIG-I protein serves as the body’s sensor for RNA-based viruses — such as hepatitis C, dengue, influenza, rabies and ebola — in the body. Once the virus infects cells, this protein recognizes its RNA, binds to it and activates, sending a signal to the rest of the body to fight against the invader, he said, adding that its mechanism of activation was unknown until now.

“For the first time we’re able to see how the protein binds and responds to RNA triggers,” Luo said. “We can now appreciate how RIG-I has evolved to carry out its job.”

He explained that the double stranded RNA that makes up the RIG-I protein complex is covered with specialized endings, joined together by a pincer that coordinates their movement. Luo said the existence of this pincer was unknown before the team’s discovery.

The hardest part of the project involved creating a homogeneous and stable solution that would yield good crystals of the RIG-I, Luo said.

“We spent almost a year getting good crystals, but once you do…the rest is straightforward,” hesaid.

But therapies based on this project will still take some time to develop, Luo said. He added that the team plans to collaborate with scientists in other fields and doctors as they work towards this goal. In addition, the team plans to continue investigating the protein itself, focusing on certain viruses that are able thwart RIG-I by inhibiting it, Luosaid.

Zhijian Chen, a professor of molecular biology at the University of Texas Southwestern Medical Center,agreed on the importance of this research in understanding the body’s response to viruses.

“It is a beautiful study,” he said.“The structures shown in this paper provide a detailed view of how the viral sensor RIG-I recognizes viral RNA.”

The project, which took almost two years to complete, was funded by Howard Hughes Medical Institute in Chevy Chase, Maryland.

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