page_title: M2 proton channel
section_title: Structure
hierarchical_section_title: M2 proton channel / Structure
caption_attribution_description: English: Cartoon representation of the molecular structure of protein registered with 1nyj code. Deutsch: Grafik des Molekularstruktur von jenem Protein, das mit 1nyj code registriert ist. Plattdüütsch: Grafik, de de Molekularstruktur von dat Protein wiest, dat mit’n Kood 1nyj registreert is.
context_page_description: The Matrix-2 protein is a proton-selective viroporin, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer, where the units are helices stabilized by two disulfide bonds, and is activated by low pH. The M2 protein is encoded on the seventh RNA segment together with the M1 protein. Proton conductance by the M2 protein in influenza A is essential for viral replication.
  Influenza B and C viruses encode proteins with similar function dubbed "BM2" and "CM2" respectively. They share little similarity with M2 at the sequence level, despite a similar overall structure and mechanism.
context_section_description: In influenza A virus, M2 protein unit consists of three protein segments comprising 97 amino acid residues: (i) an extracellular N-terminal domain (residues 1–23); (ii) a transmembrane segment (TMS) (residues 24–46); (iii) an intracellular C-terminal domain (residues 47–97). The TMS forms the pore of the ion channel. The important residues are the imidazole of His37 (pH sensor) and the indole of Trp41 (gate). This domain is the target of the anti influenza drugs, amantadine and its ethyl derivative rimantadine, and probably also the methyl derivative of rimantadine, adapromine. The first 17 residues of the M2 cytoplasmic tail form a highly conserved amphipathic helix.
  The amphipathic helix residues (46–62) within the cytoplasmic tail play role in virus budding and assembly. The influenza virus utilizes these amphipathic helices in M2 to alter membrane curvature at the budding neck of the virus in a cholesterol dependent manner. The residues 70–77 of cytoplasmic tail are important for binding to M1 and for the efficient production of infectious virus particles. This region also contains a caveolin binding domain (CBD). The C-terminal end of the channel extends into a loop (residues 47–50) that connects the trans membrane domain to the C-terminal amphipathic helix. (46–62). 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), 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).
  The two structures also suggest different binding sites for the adamantane class of anti-influenza drugs. 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. However, a recent solid state NMR spectroscopy structure shows that the M2 channel has two binding sites for amantadine, one high affinity site is in the N terminal lumen, and a second low affinity site on the C terminal protein surface.
caption: the closed state structure of m2 protein h+ channel by solid state nmr spectroscopy
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