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| Grenoble/Heidelberg, 25 February 2007 |
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| A first glimpse of the influenza replication machine
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![Crystal structure of the influenza polymerase domain [red] interacting with the human protein importin α5 [blue] involved in nuclear transport](press25feb07_s.jpg) |
Crystal structure of the influenza polymerase domain [red] interacting with
the human protein importin α5 [blue] involved in nuclear transport |
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The first 3D structure from a key influenza protein sheds light on transmission of
flu between birds and humans
Press
Release 25 February 2007 [PDF]
In 1918, 50 million
people died during a worldwide influenza pandemic caused by
mutation of a bird-specific strain of the influenza virus. Recently
H5N1, another highly infectious avian strain has caused outbreaks
of bird flu around the world. There is great concern that
this virus might also mutate to allow human-to-human transmission
and cause another catastrophic pandemic. Specific mutations
in a viral protein, the polymerase, contribute to the ability of
the bird virus to jump the species barrier to humans. Researchers
from the European Molecular Biology Laboratory [EMBL] in
Grenoble and Heidelberg, the Institut de Biologie Structurale
[IBS] and the Unit of Virus
Host Cell Interactions [UVHCI]*, both in Grenoble, have now
produced the first 3-dimensional image of part of this key protein.
The study, which is published in the current issue of Nature
Structural and Molecular Biology, investigates the structure and
function of the protein and sheds light on how polymerase mutations
contribute to transmission of avian flu to humans.
Upon infection the influenza virus starts multiplying in the cells
of an infected host. The polymerase is crucial in this process
because it copies the viral genome and directs the production of
its proteins. Interfering with polymerase function would prevent
the virus replicating, thereby reducing the spread of the virus and
the severity of the infection.
"For many years scientists have tried to understand the flu polymerase
and to look for weak points that could be targeted by
drugs," says Darren Hart, whose team participated in the research
at EMBL Grenoble. "But no one could get enough protein to
analyse its structure. We developed a way to use robots to screen
tens of thousands of experimental conditions and discovered a
piece of the influenza polymerase that we could work with. It is a
small part of the entire protein, but it provides interesting insights
into how the protein works and how mutations may affect host
range."
Together with scientists at the IBS they visualized the atomic
structure of the protein and discovered a previously overlooked
signal that labels it for transport to the human nucleus where the
genetic material of the virus is replicated. Cell microscopy studies
at EMBL Heidelberg revealed that the human nuclear transport
protein, importin alpha, recognises this signal and shuttles the
polymerase into the nucleus.
To find out how the polymerase and
importin interact, Stephen Cusack, head of EMBL Grenoble, and
collaborators at the UVHCI, used the high intensity X-ray source
of the European Synchrotron Radiation Facility to generate a
high-resolution image of the two proteins interacting with each
other. The image revealed that mutations known to play a role in
the transmission of avian influenza virus to mammals were located
within, or close to, this site of interaction. This suggests that
mutations may affect the efficiency of nuclear transport and
through this the ability of the virus to replicate in different
species.
"Interfering with polymerase function could provide new ways to
treat or prevent flu," says Cusack, "but this will require a detailed
picture of the rest of the polymerase. This is what we are aiming
for in our new FLUPOL project. In a joint effort with other
European laboratories, and with financial support by the
European Commission, we will explore both structure and function
of this key drug target and try to characterise other mutations
implicated in bird-to-human transmission."
* The Unit of Virus Host Cell Interactions is a joint unit of the Centre National de la
Recherche Scientifique [CNRS], the Université Joseph-Fourier in Grenoble and EMBL.
Source Article
F. Tarendeau, J. Boudet, S. Cusack, D.J. Hart et al. Structure and nuclear import function of the C-terminal domain of influenza virus
polymerase PB2 subunit, Nature Structural and Molecular Biology, 25 February 2007
Press Contact
Anna-Lynn Wegener
Press Officer
EMBL Heidelberg
Tel: +49 6221 387-8452
Email: wegener@embl.de |
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![Crystal structure of the influenza polymerase domain [red] interacting with the human protein importin α5 [blue] involved in nuclear transport](press25feb07_l.jpg)