Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
The A/M2 protein of influenza A virus forms a tetrameric proton-selective pH-gated ion channel. The H(37)xxxW(41) motif located in the channel pore is responsible for its gating and proton selectivity. Channel activation most likely involves protonation of the H37 residues, while the conductive state of the channel is characterized by two or three charged His residues in a tetrad. A/M2 channel activity is inhibited by the antiviral drug amantadine. Although a large number of functional amantadine-resistant mutants of A/M2 have been observed in vitro, only a few are observed in highly transmissible viruses in the presence or absence of amantadine. We therefore examined 49 point mutants of the pore-lining residues, representing both natural and nonnatural variants. Their ion selectivity, amantadine sensitivity, specific activity, and pH-dependent conductance were measured in Xenopus oocytes. These measurements showed how variations in the sequence lead to variations in the proton conduction. The results are consistent with a multistep mechanism that allows the protein to fine-tune its pH-rate profile over a wide range of proton concentrations, hypothesized to arise from different protonation states of the H37 tetrad. Mutations that give native-like conductance at low pH as well as minimal leakage current at pH 7.0 were surprisingly rare. Moreover, the results are consistent with a location of the amantadine-binding site inside the channel pore. These findings have helped to define the set of functionally fit mutants that should be targeted when considering the design of novel drugs that inhibit amantadine-resistant strains of influenza A virus.
Abed,
Generation and characterization of recombinant influenza A (H1N1) viruses harboring amantadine resistance mutations.
2005, Pubmed
Abed,
Generation and characterization of recombinant influenza A (H1N1) viruses harboring amantadine resistance mutations.
2005,
Pubmed Balannik,
The oligomeric state of the active BM2 ion channel protein of influenza B virus.
2008,
Pubmed Betakova,
Influence of residue 44 on the activity of the M2 proton channel of influenza A virus.
2005,
Pubmed Beumer,
Whole-mount immunohistochemistry on Xenopus embryos using far-red fluorescent dyes.
1995,
Pubmed
,
Xenbase Bright,
Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States.
2006,
Pubmed Bright,
Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern.
2005,
Pubmed Cady,
Structure of amantadine-bound M2 transmembrane peptide of influenza A in lipid bilayers from magic-angle-spinning solid-state NMR: the role of Ser31 in amantadine binding.
2009,
Pubmed Cady,
Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers.
2010,
Pubmed Chen,
Proton transport behavior through the influenza A M2 channel: insights from molecular simulation.
2007,
Pubmed Chizhmakov,
Selective proton permeability and pH regulation of the influenza virus M2 channel expressed in mouse erythroleukaemia cells.
1996,
Pubmed Chizhmakov,
Differences in conductance of M2 proton channels of two influenza viruses at low and high pH.
2003,
Pubmed Deyde,
Genomic events underlying the changes in adamantane resistance among influenza A(H3N2) viruses during 2006-2008.
2009,
Pubmed Deyde,
Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide.
2007,
Pubmed Furuse,
Large-scale sequence analysis of M gene of influenza A viruses from different species: mechanisms for emergence and spread of amantadine resistance.
2009,
Pubmed Grambas,
Maturation of influenza A virus hemagglutinin--estimates of the pH encountered during transport and its regulation by the M2 protein.
1992,
Pubmed Hay,
The molecular basis of the specific anti-influenza action of amantadine.
1985,
Pubmed Howard,
Sequence determinants of the energetics of folding of a transmembrane four-helix-bundle protein.
2002,
Pubmed Hu,
The chemical and dynamical influence of the anti-viral drug amantadine on the M2 proton channel transmembrane domain.
2007,
Pubmed Hu,
Histidines, heart of the hydrogen ion channel from influenza A virus: toward an understanding of conductance and proton selectivity.
2006,
Pubmed Humphrey,
VMD: visual molecular dynamics.
1996,
Pubmed Jing,
Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel.
2008,
Pubmed
,
Xenbase Khurana,
Molecular dynamics calculations suggest a conduction mechanism for the M2 proton channel from influenza A virus.
2009,
Pubmed Krumbholz,
High prevalence of amantadine resistance among circulating European porcine influenza A viruses.
2009,
Pubmed Lamb,
Influenza virus M2 protein is an integral membrane protein expressed on the infected-cell surface.
1985,
Pubmed Lear,
Association of a model transmembrane peptide containing gly in a heptad sequence motif.
2004,
Pubmed Lin,
Definitive assignment of proton selectivity and attoampere unitary current to the M2 ion channel protein of influenza A virus.
2001,
Pubmed Mould,
Permeation and activation of the M2 ion channel of influenza A virus.
2000,
Pubmed
,
Xenbase Ohigashi,
An amantadine-sensitive chimeric BM2 ion channel of influenza B virus has implications for the mechanism of drug inhibition.
2009,
Pubmed Okada,
Protonation of histidine and histidine-tryptophan interaction in the activation of the M2 ion channel from influenza a virus.
2001,
Pubmed Pielak,
Mechanism of drug inhibition and drug resistance of influenza A M2 channel.
2009,
Pubmed Pinto,
The M2 proton channels of influenza A and B viruses.
2006,
Pubmed Pinto,
Controlling influenza virus replication by inhibiting its proton channel.
2007,
Pubmed Schmidtke,
Amantadine resistance among porcine H1N1, H1N2, and H3N2 influenza A viruses isolated in Germany between 1981 and 2001.
2006,
Pubmed Schnell,
Structure and mechanism of the M2 proton channel of influenza A virus.
2008,
Pubmed Shimbo,
Ion selectivity and activation of the M2 ion channel of influenza virus.
1996,
Pubmed
,
Xenbase Shiraishi,
High frequency of resistant viruses harboring different mutations in amantadine-treated children with influenza.
2003,
Pubmed Simonsen,
The genesis and spread of reassortment human influenza A/H3N2 viruses conferring adamantane resistance.
2007,
Pubmed Stouffer,
Sequence determinants of a transmembrane proton channel: an inverse relationship between stability and function.
2005,
Pubmed Stouffer,
Structural basis for the function and inhibition of an influenza virus proton channel.
2008,
Pubmed Stouffer,
The interplay of functional tuning, drug resistance, and thermodynamic stability in the evolution of the M2 proton channel from the influenza A virus.
2008,
Pubmed
,
Xenbase Sugrue,
Specific structural alteration of the influenza haemagglutinin by amantadine.
1990,
Pubmed Suzuki,
Emergence of amantadine-resistant influenza A viruses: epidemiological study.
2003,
Pubmed Tang,
The gate of the influenza virus M2 proton channel is formed by a single tryptophan residue.
2002,
Pubmed
,
Xenbase Venkataraman,
Chemical rescue of histidine selectivity filter mutants of the M2 ion channel of influenza A virus.
2005,
Pubmed
,
Xenbase Wang,
Activation of the M2 ion channel of influenza virus: a role for the transmembrane domain histidine residue.
1995,
Pubmed
,
Xenbase Wharton,
Role of virion M2 protein in influenza virus uncoating: specific reduction in the rate of membrane fusion between virus and liposomes by amantadine.
1994,
Pubmed Wu,
A computational study of the closed and open states of the influenza a M2 proton channel.
2005,
Pubmed Yi,
A secondary gate as a mechanism for inhibition of the M2 proton channel by amantadine.
2008,
Pubmed Yi,
Conformational heterogeneity of the M2 proton channel and a structural model for channel activation.
2009,
Pubmed Zebedee,
Influenza A virus M2 protein: monoclonal antibody restriction of virus growth and detection of M2 in virions.
1988,
Pubmed
