Two new papers focus on the structure of a protein that could hold the key to new anti-flu drugs

New details about the structure of an influenza protein that is a key drug target have been revealed in separate studies by groups in the US. The two studies provide insights into the workings of the protein machinery that the virus needs to infect cells. 

In the cell, the flu virus is taken up in compartments called endosomes, but in order to infect, it has to force its genetic information inside. The M2 protein, which straddles the outer membrane of the virus, is a pH-activated trigger for this process. At around pH 6, a pore in the tetrameric protein conducts hydrogen ions from the cell to the inside of the virus.


The M2 protein is a key target in anti-flu drug development

Both studies, published back-to-back in Science, use solid-state nuclear magnetic resonance to probe the fine structure of the M2 channel protein and propose mechanisms for proton transfer - in each, histidine residues in the pore play a central role. While Mei Hong’s team at Iowa State University focused on a short segment of the protein containing the crucial histidines,1 Timothy Cross, Huan-Xiang Zhou and colleagues at Florida State University looked at a larger portion, but used simulations to propose a more detailed mechanism for proton transfer.2

Zhou and Hong grant that there are ’no major disagreements’ between their studies, which broadly suggest a shuttling model driven by rapid protonation and deprotonation of histidines, relaying hydrogen ions to the interior of the virus. But according to Zhou, Hong’s proposed mechanism omits a core component of the proton shunting machinery - a tryptophan residue. 

’They basically say the proton is handed to histidine and then gets released to the other side,’ says Zhou. ’I think the tryptophan is actually a very integral part of this mechanism and I think not having the involvement of a tryptophan is too simplistic.’ In Zhou’s model, the proton is transferred from water to histidine, through a tryptophan to another water molecule. 

Hong admits that simulations can provide greater detail than her team’s more experimental approach, but she ’wouldn’t necessarily agree’ with the finer points of Zhou’s work. ’I would say that the direct experimental result is more trustworthy,’ she says. ’But there’s more we can study by looking at the interaction of tryptophan with histidine and that will be the future.’ 

Jason Schnell, who studies the flu protein at the University of Oxford, UK, says M2 is a particularly difficult protein to work with and applauds both groups’ efforts, although he liked different aspects of each paper. ’I felt like they should have got together and found an ideal system to work in,’ he says. ’I like the construct that the Florida group used but I like the experiments that the Iowa group used.’ He does, however, point out that the lipid bilayers used by both groups as synthetic mimics for the viral membrane don’t yet offer the same resolution as previous studies carried out in detergents, including crystallographic studies. 

The new studies support the idea that interfering with the histidine components of the shuttling mechanism might produce a more effective anti-flu drug - the aim is to achieve this for mutant strains that are resistant to old flu drugs. The Cross-Zhou team is already screening for compounds based directly on its mechanism. 

Hayley Birch