NA structural overview

NA structure

This overview of the NA is meant to provide an introduction to the structure of the tetrameric influenza glycoprotein. Here we consider a homology model for the HK168 strain. The sequence (from Kim) is given below:

MNPNQKIITIGSVSLTIATVCFLMQIAILVTTVTLHFKQYECDSPASNQVMPCEPIIIER

NITEIVYLNNTTIEKEICPKVVEYRNWSKPQCQITGFAPFSKDNSIRLSAGGDIWVTREP

YVSCDHGKCYQFALGQGTTLDNKHSNDTIHDRIPHRTLLMNELGVPFHLGTRQVCIAWSS

SSCHDGKAWLHVCITGDDKNATASFIYDGRLVDSIGSWSQN-ILRTQESECVCINGTCTV

VMTDGSASGRADTRILFIEEGKIVHISPLSGSAQHVEECSCYPRYPGVRCICRDNWKGSN

RPVVDINMEDYSIDSSYVCSGLVGDTPRNDDRSSNSNCRNPNNERGNQGVKGWAFDNGDD

VWMGRTISKDLRSGYETFKVIGGWSTPNSKSQINRQVIVDSDNRSGYSGIFSVEGKSCIN

RCFYVELIRGRKQETRVWWTSNSIVVFCGTSGTYGTGSWPDGANINFMPI

All residues are referred to using N2 numbering. The images shown below can be found in presentation format in the PPT and PDF files linked below, or downloaded (along with some extra views) in this zip file.

You can also download the .pse file used to create these images. If you want to view the NA in the same was as the images below, you can use the view command i.e. 'view top4mer, recall' will give you a view appropriate for the 4mer looking down on top of it. Here is the full list of saved views: top4mer, side4mer, side1mer, side1mer2, top1mer, zoomout1mer.

Note: if you try to produce ray-traced images, you might need to reduce the 'hash_max' setting unless you have a lot of RAM in your system (about 4Gb). You may also find that DANA has moved away from the active site if you are using an old version of Pymol. This may also mean that the saved views are incorrect. If this is a real problem, let me know and I will try to correct it.

NA exists in the viral membrane as a tetramer (4mer). Each monomer (1mer) consists of a globular box-like head containing the enzymatic active site. The head is supported by a 'stalk' region for which there is no structural information available. It is shown as an extended chain here simply for reference. David B is looking for possible folds this region could make. Below this is the hydrophobic transmembrane helix and finally a small cytoplasmic domain. DANA (the product of the ester hydrolysis reaction) shown here and in other images, is docked by alignment to a H1 crystal structure with low sequence identity. As a result, its position is approximate and is shown for reference only. The exactly position and demarkation of the stalk and transmembrane helix is not known, hence the question marks.

8 positions have been identified as residues in direct contact with the glycan during binding and catalysis.

R118, D151, R152, R224, E276, R292, R371, Y406

They are highly conserved:

A second set of 11 highly conserved residues are found around the NA active site, directly supporting the catalytic residues:

E119, R156, W178, S179, D/N198, I222, E227, H274, E277, N294, E425

These are referred to as the 'framework' residues:

As before, DANA is only shown here for reference. This is not a correct docked conformation:

NA is tetrameric (4mer) – and the interface regions are shown here within dashed boxes. In order to maintain the stability of the 4mer, we expect these residues to be much less tolerant to mutation than those on exposed loops:

The other three chains of the NA monomer are now shown in metallic blue:

A top-down view of the NA 4mer showing the position of the active site:

Finally, a side view of the NA 4mer illustrates that the active site is quite deep and the loops surrounding it are likely to be highly antigenic, and affect the binding ability of NA (without destroying catalytic activity):