Knowledge of protein structure may shed light on avian flu virus

HOUSTON -- (May 22, 2006) -- By determining the structure of an important protein that is part of the influenza A virus, researchers at Baylor College of Medicine in Houston may have found clues to explain the virus' virulence and also the dangers posed by the current strains of avian flu killing fowl and some people around the world.

The protein – NS1 – has two major areas called domains, said Dr. B.V. Venkataram Prasad, professor of biochemistry and molecular biology at BCM. The structure of one – the double stranded RNA binding domain – was determined previously. Prasad and Zachary A. Bornholdt, a graduate student in the BCM Graduate School of Biomedical Sciences and in Prasad's laboratory, determined the structure of the second – the effector domain – and in doing so, found that some of the mutations or changes in the avian flu virus, known also as H5N1, occur in this protein and could be mapped on to the structure. A report of their work appears in the current issue of the journal Nature Structural and Molecular Biology.

In particular, said Bornholdt, in recent H5N1 strains, NS1 has a deletion of genetic material that truncates a linker region, which could play a role in how the two different parts or domains of the virus interact with other molecules. It is the relationship between these two domains that causes the virulence seen in recent forms of the avian flu virus.

NS1 actually hinders the cell's ability to protect itself via the immune system.

"The mutations (seen in the version of the avian influenza virus) allow the virus to counteract the immune response more efficiently," said Prasad.

Prasad and Bornholdt emphasize that much of what they surmise from the structure of this part of the virus needs to be tested in the laboratory.

"What we have done is put this structure out there and say that this is what might be happening," said Prasad. "These are proposals or hypotheses."

Knowing where NS1 binds to certain critical molecules in the cell makes it possible to design drugs that will interrupt that interaction, said Prasad and Bornholdt. By doing so, it could interrupt NS1's ability to disrupt the immune response.

Bornholdt said such a drug would have an advantage over the current ones because it could stop the virus during the course of the disease. Current drugs must be taken very early in the infection to be effective.

Because many viruses have proteins similar to NS1 that serve similar functions, it also hints at the possibility that it might be possible to design drugs that could interrupt this activity in many different viruses, the scientists said.

Funding for this project came from the National Institutes of Health and the Welch Foundation.