Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers

Double life of flu virus protein The current H1N1 strain pandemic virus is resistant to the established antiviral agents amantadine and rimantadine, which target the M2 protein, a multifunctional membrane-spanning proton channel. The structure of this channel has been a subject of some controversy, since an X-ray crystal structure of part of the M2 channel showed electron density that corresponded to a single molecule of amantadine in the N-terminal half of the pore, whereas a solution NMR structure of a larger portion of the channel showed four rimantadine molecules bound to the C-terminal lipid-facing surface of the helices. The matter now appears resolved with the publication of the high-resolution structure of the M2 channel in a phospholipid bilayer, determined using solid-state NMR spectroscopy. This reveals two amantadine-binding sites: a high-affinity site in the N-terminal channel lumen and a low-affinity site on the C-terminal protein surface. This work could be of value for the development of new anti-influenza drugs, an important goal since the 2009 seasonal virus is amantadine-sensitive but resistant to Tamiflu, raising the possibility that multiply resistant virus types might emerge in future.