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PDBsum entry 2ht8
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References listed in PDB file
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Key reference
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Title
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The structure of h5n1 avian influenza neuraminidase suggests new opportunities for drug design.
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Authors
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R.J.Russell,
L.F.Haire,
D.J.Stevens,
P.J.Collins,
Y.P.Lin,
G.M.Blackburn,
A.J.Hay,
S.J.Gamblin,
J.J.Skehel.
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Ref.
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Nature, 2006,
443,
45-49.
[DOI no: ]
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PubMed id
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Abstract
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The worldwide spread of H5N1 avian influenza has raised concerns that this virus
might acquire the ability to pass readily among humans and cause a pandemic. Two
anti-influenza drugs currently being used to treat infected patients are
oseltamivir (Tamiflu) and zanamivir (Relenza), both of which target the
neuraminidase enzyme of the virus. Reports of the emergence of drug resistance
make the development of new anti-influenza molecules a priority. Neuraminidases
from influenza type A viruses form two genetically distinct groups: group-1
contains the N1 neuraminidase of the H5N1 avian virus and group-2 contains the
N2 and N9 enzymes used for the structure-based design of current drugs. Here we
show by X-ray crystallography that these two groups are structurally distinct.
Group-1 neuraminidases contain a cavity adjacent to their active sites that
closes on ligand binding. Our analysis suggests that it may be possible to
exploit the size and location of the group-1 cavity to develop new
anti-influenza drugs.
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Figure 2.
Figure 2: Molecular surfaces of group-1 and group-2
neuraminidases with bound oseltamivir showing the 150-cavity in
the group-1 structure that arises because of the distinct
conformation of the 150-loop. a, b, N1 (a; green) and N9 (b;
yellow) shown in surface representation with the protein main
chain shown in 'worm' representation. c, Superposition of the
active sites of apo-N1 (green) and N1 complexed with oseltamivir
(blue). Part of the electron density map from a low-resolution
(5.5 Å) difference Fourier calculated between apo-N1 and
oseltamivir-bound N1 data sets is shown in blue to indicate the
position of the 150-cavity.
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Figure 3.
Figure 3: Oseltamivir binding to the active sites of group-1
neuraminidases. a, Superposition of the active sites of N8
after a 30-min soak (dark blue) and a 3-day soak (cyan) with 20
 M
oseltamivir. There are small changes in the position of Glu 119
and the inhibitor when the 150-loop closes after the longer
soaking time. b, Superposition of the active sites of N8 with
bound oseltamivir after the 3-day soak with 20 M
inhibitor (cyan) with N1 soaked for 30 min in 0.5 mM inhibitor
(green). In this case, the structures of the two different
subtypes of neuraminidase from group-1 are remarkably similar.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2006,
443,
45-49)
copyright 2006.
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