Newly described 'dragon' protein could be key to bird flu
cure
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ARGONNE, Ill. (July 15, 2008)—Scientists and researchers have taken a big
step closer to a cure for the most common strain of avian influenza, or "bird
flu," the potential pandemic that has claimed more than 200 lives and
infected nearly 400 people in 14 countries since it was identified in 2003.
Researchers at the U.S. Department of Energy's (DOE) Argonne National Laboratory,
in conjunction with scientists from China and Singapore, have crystallized
and characterized the structure of one of the most important protein complexes
of the H5N1 virus, the most common strain of bird flu.
All viruses, including H5N1, contain only a small number of proteins that
govern all of the viruses' functions. In H5N1, perhaps the most important of
these proteins is RNA polymerase, which contains the instructions that allows
the virus to copy itself along with all of its genetic material. The Argonne
study focused on H5N1's RNA polymerase protein, which contains three subunits:
PA, PB1 and PB2.
After performing X-ray crystallography on the protein crystals at Argonne's
Structural Biology Center at the Advanced
Photon Source, the researchers saw
a surprising resemblance in the protein structure's image. "When we mapped
out the PA subunit, it looked very much like the head of a dragon," said
Argonne biophysicist Andrzej Joachimiak. "One domain looked like the dragon's
brains, and the other looked like its mouth."
During RNA replication – the phase during which the virus "reproduces" – all
three of the subunits of the protein assemble themselves in a particular configuration.
In order for this congregation to take place, the researchers determined the
end of the PB1 subunit has to insert itself and bind to the "dragon's
mouth" part of the PA subunit.
This unexpected relationship between the two subunits could inspire a number
of different therapies or vaccines for H5N1 that rely on muzzling the "dragon's" jaws
with another molecule or chemical compound that would block the PB1 subunit's
access to the PA site, according to Joachimiak. "If we can put a bit in
the dragon's mouth, we can slow or even potentially someday stop the spread
of avian flu," he said. "Since we are talking about a relatively
small protein surface area, finding a way to inhibit RNA replication in H5N1
seems very feasible."
Joachimiak hopes to more precisely identify the types of compounds that could
inhibit RNA replication in H5N1 by looking at the atomic-level grooves and
pockets within the PA "mouth" region. According to Joachimiak, scientists
must gain a more thorough understanding of the geometry of that small region
in order to effectively synthesize drugs that could prevent the further spread
of bird flu.
Argonne researchers Joachimiak and Rongguang Zhang collaborated with
Zihe Rao and Yingfang Liu, both members of the Institute of Biophysics of Chinese
Academy of Sciences. Rao is one of the most influential Chinese crystallographers
and biophysicists, Joachimiak said. The protein samples were manufactured
in China and crystals were shipped to Argonne for data collection and structural
analysis.
The results of the study will be reported in an upcoming issue of Nature and
can be found online at http://dx.doi.org/10.1038/nature07120. The work was
funded by the National
Natural Science Foundation of China as well as the Chinese
Ministry of Science and Technology and the U.S. Department of Energy's Office
of Biological
and Environmental Research.
Argonne National Laboratory seeks solutions to pressing national problems in science and technology.
The nation's first national laboratory, Argonne conducts leading-edge basic
and applied scientific research in virtually every scientific discipline. Argonne
researchers work closely with researchers from hundreds of companies, universities,
and federal, state and municipal agencies to help them solve their specific
problems, advance America 's scientific leadership and prepare the nation for
a better future. With employees from more than 60 nations, Argonne is managed
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the U.S.
Department of Energy's Office
of Science.
By Jared Sagoff.
For more information, please
contact Steve McGregor (630/252-5580 or media@anl.gov)
at Argonne.
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