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| Grenoble, 16 June 2006 |
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| Cracking a virus protection shield
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![Six nucleoproteins [in different colours] bind side-by-side on one RNA molecule [black]](press16jun06-1s.jpg) |
| Six nucleoproteins [in different colours] bind side-by-side on one RNA
molecule [black] |
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| Winfried Weissenhorn, EMBL Grenoble |
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Press
Release 16 June 2006 [PDF]
Français
Scientists reveal the structure of a protein that packages the viral genome and
helps viruses to replicate while avoiding human immune reactions
Ebola, measles and rabies are serious
threats to public health in developing countries. Despite different
symptoms all of the diseases are caused by the same class of viruses
that unlike most other living beings carry their genetic information
on a single RNA molecule instead of a double strand of
DNA. Now researchers from the Institut de Virologie
Moléculaire et Structurale [IVMS] and the Outstation of the
European Molecular Biology Laboratory [EMBL] in Grenoble
have obtained a detailed structural picture of a protein that allows
the rabies virus to withstand the human immune response and
survive and replicate in our cells. The study that is published in
this week's online edition of Science suggests new potential drug
targets in rabies and sheds light on how similar approaches can
help fighting other viral diseases.
When the rabies virus enters a human cell through the membrane,
the RNA molecule that carries its genes is transported into
the centre of the cell. Here it redirects the cellular machinery of
the host to produce many new copies of the virus that go on to
infect more cells. One molecule that is crucial in this process is a
viral protein called nucleoprotein. The protein ensures that on its
way through the cell the virus RNA is not destroyed by the
immune response of the host.
"Nucleoprotein is vital for the rabies virus," says Rob Ruigrok,
Head of the IVMS. "It is one of the few proteins that the virus
brings into the host cell and it wraps around the RNA like a protection
shield. Without this shield the RNA would be degraded by
the enzymes of the human immune system that try to eliminate
the invader."
To investigate how exactly this protection shield works, Aurélie
Albertini from Ruigrok's team obtained crystals of nucleoprotein
bound to RNA. Examining the crystals with high-intensity X-ray
sources at the European Synchrotron Radiation Facility [ESRF],
Amy Wernimont from Winfried Weissenhorn's group at EMBL
Grenoble produced a high-resolution image of the protein.
"Nucleoprotein acts like a clamp," says Weissenhorn. "It consists
of two domains that like two jaws clasp around the RNA strand.
Many nucleoproteins bind side-by-side along the length of an
RNA molecule and make it inaccessible for degrading enzymes
but also for the machinery needed to replicate the virus. This
means that the protection shield must be flexible and able to distinguish
between different types of enzymes trying to gain
access."
The detailed structural picture suggests that upon a signal a part
of the protein located between the two main domains might act as
a hinge that moves the upper jaw out of the way when time for
replication has come.
"This dynamic mechanism makes nucleoproteins an excellent
drug target," says Ruigrok, "Small agents that bind to the protein
in such a way to block its flexibility and keep it in the closed state,
would prevent replication of the virus and would stop it from
spreading."
Rabies virus shares this protection strategy with other viruses of
its class; in Ebola, measles and Borna virus similar complexes of
RNA and nucleoproteins have been found.
"This means that our results do not only have implications for the
design of new drugs against rabies, but they suggest new therapeutic
approaches in a variety of diseases, some of which are
much more threatening than rabies. On a different note, the conservation
of the nucleoprotein system also leaves room for evolutionary
speculations about common ancestors and primordial
infectious units of RNA viruses," Weissenhorn concludes.
Source Article
A.A.V. Albertini, A.K. Wernimont, T. Muziol, R.G.B. Ravelli, C.R. Clapier, G. Schoehn, W. Weissenhorn & R. Ruigrok. Crystal structure
of the rabies virus nucleoprotein-RNA complex, Science online, 15 June 2006
Press Contact
Anna-Lynn Wegener
Press Officer
EMBL Heidelberg
Tel: +49 +6221 387-8452
Email: wegener@embl.de |
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