PDBsum entry: 2htw

Hydrolase

PDB-id: 2htw

Asymmetric unit

Contents

Description

Header details

Header records

References

PROCHECK

Protein chain

388 a.a.

Ligands

DAN

Tools

Clefts Calculation

Biological unit, tetramer
- as defined in PDB file (see also PQS)

PDB id:

2htw

Name:

Hydrolase

Title:

N4 neuraminidase in complex with dana

Structure:

Neuraminidase. Chain: a

Source:

Influenza a virus. Organism_taxid: 11320

Biological unit:

Tetramer (from PDB file)

UniProt:

Q6XV46 (Q6XV46_9INFA)

Seq:

Struc:

Seq:

470 a.a.

Struc:

388 a.a.

Key:	PfamA domain
Secondary structure	CATH domain

Resolution:

3.50Å

R-factor:

0.217

R-free:

0.295

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

Key ref:

R.J.Russell et al. (2006). The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design.. Nature, 443, 45-49. [PubMed id: 16915235] [DOI: 10.1038/nature05114]

Date:

26-Jul-06

Release date:

05-Sep-06

Related entries:

2ht5
2ht7
2ht8
2htu
2htq
2htv
2htr
2hty
2hu0
2hu4

Quick_links

Procheck

Clefts

Surface

Key reference

DOI no: 10.1038/nature05114

Nature 443:45-49 (2006)

PubMed id: 16915235

The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design.

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.

ABSTRACT

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.

Selected figure(s)

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.

Figures were selected by an automated process.