Influenza's Tricky Resistance: Unraveling M2's Dimer Structure

Influenza A is giving scientists a run for their money with its drug-resistant variant, the S31N M2 proton channel. Lately, researchers have been concerned about how different lipid environments might affect this channel's structure. The M2 tetramer's native shape is still a hot topic among experts. Here’s what’s new: S31N M2 keeps its dimer-of-dimers structure no matter the type or amount of lipids it’s mixed with—up to 180 lipids per tetramer! NMR scans clearly spot the signature resonances of this M2 configuration (spanning residues 18-60 or 18-62) blended with lipids. These scans also show that two particular isoleucine residues, which appear as upfield-shifted alpha carbon resonances typical of extended structures, match well with a specific side-chain rotamer state and helical backbone geometry. This aligns with what we expect from a native transmembrane helical fold.The pH-sensing H37 residues in S31N M2 show symmetry breaking, seen via peak doubling. This characteristic is stable, according to the reference strain Udorn/1972(H3N2). However, things change for Columbia/2014/(H3N2) M2, which has sequence variations in its amphipathic helices, leading to a drastically different spectrum. This contrast highlights how the amphipathic helices can allosterically influence the pH-sensing residues.