NSF PR 99-17 - March 15, 1999
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Researchers Uncover 3-D Structure Of Virus Replication
Technique
Development of New Anti-Viral
Agents Possible
National Science Foundation (NSF)-funded scientists
at the Massachusetts Institute of Technology and Northwestern
University Medical School have uncovered the structural
basis of an elusive replication technique that allows
viruses, especially retroviruses, to commandeer cells
to manufacture the proteins they need for their own
survival. The results appear in a paper published
for the March 1999 issue of Nature Structural
Biology.
"For many years, scientists have studied a virus'
ability to create an RNA structure called a pseudoknot,
which allows it to control genetic material for its
own purposes via a process called ribosomal frameshifting,"
explains Kamal Shukla, director of NSF's biophysics
program, which funded the research. "Until now, the
detailed three-dimensional structure of the pseudoknot
- so called because the RNA is not truly knotted,
but tightly bound together -- has not been known."
The RNA pseudoknot formed by the beet western yellow
virus has been crystallized, and the three-dimensional
structure reveals many unusual features, the authors
of the study report. Ribosomal frameshifting also
is used by the AIDS virus.
"This research will help us uncover some of the methods
that viruses use to regulate the production of components
that are essential to viral replication. Knowledge
of this mechanism may allow us to develop ways to
modify that process and thus lead to the development
of new anti-viral agents," said Alexander Rich, a
biophysicist at MIT and one of the study's authors.
The work provides information that will allow researchers
to understand which features of the pseudoknot formation
facilitate ribosomal frameshifting by introducing
mutations or changes in the pseudoknot.
Viruses have developed ingenious systems for invading
cells and making more copies of themselves. One of
the systems that is used in many viruses, including
most retroviruses (the most famous of which is responsible
for AIDS) involves inducing changes in the way the
virus' genetic material is translated to produce the
next generation. The virus needs to synthesize two
different proteins. Typically, the first protein is
involved in building the virus and the second is an
enzyme, usually a polymerase, used in replicating
the virus' nucleic acid, or genetic building blocks.
But the virus needs many copies of the structural
protein and a smaller number of the polymerase proteins,
so the virus developed a novel system for regulating
the production of these two proteins. It involves
the use of ribosomal frameshifting.
The decision to frameshift or not to frameshift depends
on whether the pseudoknot unravels when it collides
with the ribosome, Rich said. If it does not unravel,
the ribosome can slide back one nucleotide and then
make a fusion protein, involving both the structural
protein and the polymerase. If the pseudoknot does
unravel, then only the structural protein is made,
but not the polymerase.
This work is also supported by the National Institutes
of Health, the National Foundation for Cancer Research,
and the National Aeronautics and Space Administration.
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