PDBsum entry 2htu

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Hydrolase PDB id
Protein chain
387 a.a.

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Key reference
Title The structure of h5n1 avian influenza neuraminidase suggests new opportunities for drug design.
Authors 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.
Ref. Nature, 2006, 443, 45-49. [DOI no: 10.1038/nature05114]
PubMed id 16915235
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.
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.
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.
The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2006, 443, 45-49) copyright 2006.
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