By Yun Xie | Published: July 29, 2008 - 10:47AM CT
Influenza A virus: H5N1.
The Influenza A virus population contains variants and subtypes that have the potential to spread virulently across the globe, including H5N1. A strain of H5N1 is behind the avian flu, which kills over 50 percent of the humans who are infected with it. H5N1 has the potential of mutating to increase its transmission efficiency among humans, making it a major concern for world health.
It is known that there are three subunits (PB1, PB2 and PA) in an Influenza A protein complex that are essential for its replication. The structures of these subunits, however, were not well understood. Thus, it was impossible to create drugs that inhibit their function. Currently, most drugs either target major antigens at the surface of the virus or specific proteins like a proton channel. Antigens and proteins vary among different types of Influenza A, so it is difficult to find drugs that work on all of them and mutations that slightly alter a protein or antigen can easily make drugs useless. Knowing the structures of the Influenza A subunits would open new avenues for drug design.
The binding site of PA(green) and PB1(orange).
In an early release paper that will appear in Nature, scientists from Japan presented the crystal structures of two large fragments of subunits PA and PB1 bound to one another. The binding of PA to PB1 is vital for viral replication and RNA polymerase activity. From the structure, the authors discovered that this crucial interaction comes from an array of hydrogen bonds and hydrophobic interfaces at the binding site. The binding sites that link PA and PB1 are highly conserved, which means that they are very similar for most variants and subtypes of Influenza A. It also means that mutations are less likely to occur in this site.
Because of these features, drugs that can bind and disrupt the interaction of PA and PB1 are likely to be effective against many viral strains and will be less likely to see the virus evolve a resistance to them. The authors' solved structures will serve as a valuable reference point for future drug design.
Nature, 2008. DOI: doi:10.1038/nature07225
