Two different high-resolution structures of truncated forms of M2 have been reported: the crystal structure of a mutated form of the M2 transmembrane region (residues 22–46),[5] as well as a longer version of the protein (residues 18–60) containing the transmembrane region and a segment of the C-terminal domain as studied by nuclear magnetic resonance (NMR).

According to the low pH crystal structure a single molecule of amantadine binds in the middle of the pore, surrounded by residues Val27, Ala30, Ser31 and Gly34.

In contrast, the NMR structure showed four rimantadine molecules bind to the lipid facing outer surface of the pore, interacting with residues Asp44 and Arg45.

When His37 is replaced with glycine, alanine, glutamic acid, serine or threonine, the proton selective activity is lost and the mutant can transport Na+ and K+ ions also.

When imidazole buffer is added to cells expressing mutant proteins, the ion selectivity is partially rescued.

[9] Acharya et al. suggested that the conduction mechanism involves the exchange of protons between the His37 imidazole moieties of M2 and waters confined to the M2 bundle interior.

Pore-lining carbonyl groups are well situated to stabilize hydronium ions via second-shell interactions involving bridging water molecules.

Moreover, protons diffusing through the channel need not be localized to a single His37 imidazole, but instead may be delocalized over the entire His-box and associated water clusters.

Subsequent membrane fusion releases the uncoated RNPs into the cytoplasm which is imported to the nucleus to start viral replication.

[13] Other important functions of M2 are its role in formation of filamentous strains of influenza, membrane scission and the release of the budding virion.

[15] Mutations conferring resistance to adamantane drugs, including amantadine and rimantadine, occur in the transmembrane region and are widespread.

[16] Resistance to adamantanes among circulating influenza A viruses varies by region but has globally increased significantly since the early 2000s.