PDBsum entry 3f5t

Viral protein

PDB id: 3f5t

Contents

Protein chain

188 a.a.

PDB id:

3f5t

Name:

Viral protein

Title:

X-ray structure of h5n1 ns1

Structure:

Nonstructural protein 1. Chain: a. Synonym: ns1. Other_details: full length a/vietnam/1203/2004(h5n1) sequence

Source:

Influenza virus. Organism_taxid: 11309. Strain: a/vietnam/1203/2004

Resolution:

2.70Å R-factor: 0.281 R-free: 0.296

Authors:

Z.A.Bornholdt,B.V.V.Prasad

Key ref:

Z.A.Bornholdt and B.V.Prasad (2008). X-ray structure of NS1 from a highly pathogenic H5N1 influenza virus. Nature, 456, 985-988. PubMed id: 18987632 DOI: 10.1038/nature07444

Date:

04-Nov-08 Release date: 25-Nov-08

Supersedes:

3eu6

Protein chain

A5A5U1  (A5A5U1_I04A1) -  Non-structural protein 1 from Influenza A virus (strain A/Vietnam/1203/2004 H5N1)

Seq: 215 a.a.

Struc: 188 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1038/nature07444

Nature 456:985-988 (2008)

PubMed id: 18987632

X-ray structure of NS1 from a highly pathogenic H5N1 influenza virus.

Z.A.Bornholdt, B.V.Prasad.

ABSTRACT

The recent emergence of highly pathogenic avian (H5N1) influenza viruses, their epizootic and panzootic nature, and their association with lethal human infections have raised significant global health concerns. Several studies have underlined the importance of non-structural protein NS1 in the increased pathogenicity and virulence of these strains. NS1, which consists of two domains-a double-stranded RNA (dsRNA) binding domain and the effector domain, separated through a linker-is an antagonist of antiviral type-I interferon response in the host. Here we report the X-ray structure of the full-length NS1 from an H5N1 strain (A/Vietnam/1203/2004) that was associated with 60% of human deaths in an outbreak in Vietnam. Compared to the individually determined structures of the RNA binding domain and the effector domain from non-H5N1 strains, the RNA binding domain within H5N1 NS1 exhibits modest structural changes, while the H5N1 effector domain shows significant alteration, particularly in the dimeric interface. Although both domains in the full-length NS1 individually participate in dimeric interactions, an unexpected finding is that these interactions result in the formation of a chain of NS1 molecules instead of distinct dimeric units. Three such chains in the crystal interact with one another extensively to form a tubular organization of similar dimensions to that observed in the cryo-electron microscopy images of NS1 in the presence of dsRNA. The tubular oligomeric organization of NS1, in which residues implicated in dsRNA binding face a 20-A-wide central tunnel, provides a plausible mechanism for how NS1 sequesters varying lengths of dsRNA, to counter cellular antiviral dsRNA response pathways, while simultaneously interacting with other cellular ligands during an infection.

Selected figure(s)

Figure 1.
Figure 1: H5N1 NS1 structure. a, Cartoon representation of the H5N1 NS1 structure as viewed looking across (top) and down onto (bottom) the main -helix of the RBD (aquamarine) that is implicated in dsRNA binding. The ED is coloured green, and the linker region orange; shown as orange dashed lines are 5 residues (75–79) not well defined in the electron density map. b, Structural alignment of H5N1 NS1 RBD (aquamarine) with H3N1 NS1 RBD^6 (ruby: PDB ID, 1AIL), and c, alignment of the H5N1 NS1 ED (green) with H1N1 NS1 ED^7 (ruby: PDB ID, 2GX9). In both b and c the alignments are oriented to display the areas of greatest deviation, namely the V22F conformational change in a loop region observed in the H5N1 RBD (b), and the movement of the -sheets in the H5N1 ED (c), both indicated by black arrows.

Figure 2.
Figure 2: RBD and ED dimer formation, and the NS1 chain. a, The RBD and ED of each NS1 molecule separately interact with their respective domains from the neighbouring NS1 molecules, related by crystallographic two-fold axes (perpendicular to plane of the paper indicated the black ovals), resulting in the formation of a chain of NS1 with alternating RBD and ED dimers. The two-fold related NS1 molecules are coloured separately in yellow and green. The residues critical to dsRNA (residues 38 and 41)^16 and CPSF (conserved residues F103, M106 and GLEWN183-187) binding^14, ^15, ^19 are coloured in blue and red, respectively. b, Superposition of H5N1 RBD dimer with the H3N2 RBD^6 dimer (in ruby; PDB ID, 1AIL); each protomeric subunit in the H5N1 RBD dimer is coloured differently in yellow and green. c, Structural alignment of the H5N1 dimer and H1N1 NS1 ED^7 dimer (in ruby; PDB ID, 2GX9), demonstrating the twisting motion (curved arrows) of the H5N1 ED monomers, with respect to H1N1 ED, towards their RBDs. Each monomer in the H5N1 NS1 dimer is coloured as in a. The dimeric interface of the H5N1 NS1 ED consists of a series of electrostatic interactions: a salt bridge between K131 and E97, hydrogen-bonding involving the side chains of T91 and R193, E196 and R200, E152 and the amide group of L95, as well as a back-bone hydrogen bond between the E96 amide group and the E152 carbonyl group. In contrast, the dimeric interactions in the H1N1 NS1 ED consists primarily of strong hydrophobic interactions along the continuous anti-parallel -sheet involving residues L90, V136 and L141 (ref. 7).

The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: Nature (2008, 456, 985-988) copyright 2008.

Figures were selected by an automated process.