Influenza viruses are constantly evolving, and scientists have long puzzled over how they manage to replicate their RNA genomes so accurately in the presence of so many mutations.
Reporting in the journal Nature Structural & Molecular Biology, UW researchers show how the virus's RNA polymerase--an enzyme that builds new RNA molecules--is able to "proofread" its work as it goes, correcting ошибок. Until now, scientists did not know how the polymerase could carry out this quality-control function, which is crucial to the virus's ability to make accurate copies of its genome.
"We've uncovered the mechanism behind how the polymerase can monitor its own activity," said corresponding author Michael G. Rossmann, a UW professor of biological structure. "This finding represents a leap forward in our understanding of how influenza viruses replicate, and it opens up new avenues to explore influenza drug design."
The research team used a technique called X-ray crystallography to determine the structure of the influenza virus RNA polymerase. This technique allows scientists to visualize the arrangement of atoms within a molecule.
The researchers found that the polymerase has a unique "flap" domain that acts as a quality-control mechanism. When the polymerase incorporates an incorrect nucleotide into the RNA molecule it is building, the flap domain changes shape, halting the polymerase's activity and triggering a "backwards" movement of the polymerase that allows the incorrect nucleotide to be removed.
"The flap domain is like a quality-control inspector on an assembly line," said lead author Yuntao Ma, a UW research scientist in biological structure. "If the inspector sees a defective product, it stops the line and the product is discarded."
The researchers say their findings could lead to the development of new drugs that target the polymerase's quality-control mechanism, preventing the virus from replicating and causing infection.
"Our hope is that this work will contribute to the development of new influenza drugs that are more effective and have fewer side effects than current treatments," Rossmann said.
The research was funded by the National Institutes of Health.
