Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus

Rudresh Acharya, Vincenzo Carnevale, Giacomo Fiorin, Benjamin G. Levine, Alexei L. Polishchuk, Victoria Balannik, Ilan Samish, Robert A. Lamb, Lawrence H. Pinto, William F. DeGrado, Michael L. Klein

Research output: Contribution to journalArticlepeer-review

197 Scopus citations


The M2 proton channel from influenza A virus is an essential protein that mediates transport of protons across the viral envelope. This protein has a single transmembrane helix, which tetramerizes into the active channel. At the heart of the conduction mechanism is the exchange of protons between the His37 imidazole moieties of M2 and waters confined to the M2 bundle interior. Protons are conducted as the total charge of the four His37 side chains passes through 2+ and 3+ with a pKa near 6. A 1.65 Å resolution X-ray structure of the transmembrane protein (residues 25-46), crystallized at pH 6.5, reveals a pore that is lined by alternating layers of sidechains and well-ordered water clusters, which offer a pathway for proton conduction. The His37 residues form a box-like structure, bounded on either side by water clusters with wellordered oxygen atoms at close distance. The conformation of the protein, which is intermediate between structures previously solved at higher and lower pH, suggests a mechanism by which conformational changes might facilitate asymmetric diffusion through the channel in the presence of a proton gradient. 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. Thus, the new crystal structure provides a possible unification of the discrete site versus continuum conduction models.

Original languageEnglish (US)
Pages (from-to)15075-15080
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number34
StatePublished - Aug 24 2010


  • Histidine protonation
  • Ion channels
  • M2 proton channel
  • Membrane proteins
  • Water clusters

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus'. Together they form a unique fingerprint.

Cite this