he M2 protein from influenza A virus forms an essential component of viral envelope. It is a 97 amino acid protein with a single transmembrane (TM) alpha-helix that assembles to form a homotetrameric channel. This pH-activated proton channel is required for acidification of the inside of the virus once engulfed by the endosome. M2 is the target of the anti-influenza drugs amantadine and rimantadine. These drugs were used prophylactically for over three decades. However, in the last few years drug-resistive mutant viruses (humans, birds, and pigs) have become wide spread. With envision to understand the proton conduction mechanism and understand the mode of action of drug(s), we have solved the crystal structures of the TM region of protein with (at 3.5A resolution, pH 5.3) and without presence of channel blocking drug amantadine (at 2.0A resolution, pH 7.3). Recently, we have determined high resolution (1.65A, pH 6.5) crystal structure of TM region of M2, striking feature is the observation of ordered water clusters confined in the channel pore. Our structure shows the drug binding site and nicely explains how mutations eliminate binding.Structures solved at various pH, and observation of well-ordered water clusters provide an insight into the proton conduction mechanism.