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.
Proc Natl Acad Sci U S A
2008 Aug 05;10531:10967-72. doi: 10.1073/pnas.0804958105.
Show Gene links
Show Anatomy links
Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel.
Jing X
,
Ma C
,
Ohigashi Y
,
Oliveira FA
,
Jardetzky TS
,
Pinto LH
,
Lamb RA
.
???displayArticle.abstract???
Influenza A and B viruses contain proton-selective ion channels, A/M2 and BM2, respectively, and the A/M2 channel activity is inhibited by the drugs amantadine and its methyl derivative rimantadine. The structure of the pore-transmembrane domain has been determined by both x-ray crystallography [Stouffer et al. (2008) Nature 451:596-599] and by NMR methods [Schnell and Chou (2008) Nature 451:591-595]. Whereas the crystal structure indicates a single amantadine molecule in the pore of the channel, the NMR data show four rimantadine molecules bound on the outside of the helices toward the cytoplasmic side of the membrane. Drug binding includes interactions with residues 40-45 with a polar hydrogen bond between rimantadine and aspartic acid residue 44 (D44) that appears to be important. These two distinct drug-binding sites led to two incompatible drug inhibition mechanisms. We mutagenized D44 and R45 to alanine as these mutations are likely to interfere with rimantadine binding and lead to a drug insensitive channel. However, the D44A channel was found to be sensitive to amantadine when measured by electrophysiological recordings in oocytes of Xenopus laevis and in mammalian cells, and when the D44 and R45 mutations were introduced into the influenza virus genome. Furthermore, transplanting A/M2 pore residues 24-36 into BM2, yielded a pH-activated chimeric ion channel that was partially inhibited by amantadine. Thus, taken together our functional data suggest that amantadine/rimantadine binding outside of the channel pore is not the primary site associated with the pharmacological inhibition of the A/M2 ion channel.
Air,
Gene and protein sequence of an influenza neuraminidase with hemagglutinin activity.
1985, Pubmed
Air,
Gene and protein sequence of an influenza neuraminidase with hemagglutinin activity.
1985,
Pubmed
Astrahan,
A novel method of resistance for influenza against a channel-blocking antiviral drug.
2004,
Pubmed
Balannik,
The oligomeric state of the active BM2 ion channel protein of influenza B virus.
2008,
Pubmed
Bauer,
The influenza virus M2 ion channel protein: probing the structure of the transmembrane domain in intact cells by using engineered disulfide cross-linking.
1999,
Pubmed
Betakova,
Influence of residue 44 on the activity of the M2 proton channel of influenza A virus.
2005,
Pubmed
Briedis,
Sequence of RNA segment 7 of the influenza B virus genome: partial amino acid homology between the membrane proteins (M1) of influenza A and B viruses and conservation of a second open reading frame.
1982,
Pubmed
Castrucci,
The cysteine residues of the M2 protein are not required for influenza A virus replication.
1997,
Pubmed
Chizhmakov,
Selective proton permeability and pH regulation of the influenza virus M2 channel expressed in mouse erythroleukaemia cells.
1996,
Pubmed
Ciampor,
Evidence that the amantadine-induced, M2-mediated conversion of influenza A virus hemagglutinin to the low pH conformation occurs in an acidic trans Golgi compartment.
1992,
Pubmed
Epand,
Effects of viral chemotherapeutic agents on membrane properties. Studies of cyclosporin A, benzyloxycarbonyl-D-Phe-L-Phe-Gly and amantadine.
1987,
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
Holsinger,
Influenza virus M2 integral membrane protein is a homotetramer stabilized by formation of disulfide bonds.
1991,
Pubmed
Holsinger,
Analysis of the posttranslational modifications of the influenza virus M2 protein.
1995,
Pubmed
,
Xenbase
Hu,
Histidines, heart of the hydrogen ion channel from influenza A virus: toward an understanding of conductance and proton selectivity.
2006,
Pubmed
Kovacs,
Transmembrane four-helix bundle of influenza A M2 protein channel: structural implications from helix tilt and orientation.
1997,
Pubmed
Lamb,
Conservation of the influenza virus membrane protein (M1) amino acid sequence and an open reading frame of RNA segment 7 encoding a second protein (M2) in H1N1 and H3N2 strains.
1981,
Pubmed
Lamb,
Influenza virus M2 protein is an integral membrane protein expressed on the infected-cell surface.
1985,
Pubmed
Ma,
Identification of the pore-lining residues of the BM2 ion channel protein of influenza B virus.
2008,
Pubmed
,
Xenbase
Martin,
Nuclear transport of influenza virus ribonucleoproteins: the viral matrix protein (M1) promotes export and inhibits import.
1991,
Pubmed
Matrosovich,
New low-viscosity overlay medium for viral plaque assays.
2006,
Pubmed
Miller,
Ion channels: coughing up flu's proton channels.
2008,
Pubmed
Mould,
Permeation and activation of the M2 ion channel of influenza A virus.
2000,
Pubmed
,
Xenbase
Mould,
Influenza B virus BM2 protein has ion channel activity that conducts protons across membranes.
2003,
Pubmed
,
Xenbase
Neumann,
Generation of influenza A viruses entirely from cloned cDNAs.
1999,
Pubmed
Paterson,
Influenza B virus BM2 protein is an oligomeric integral membrane protein expressed at the cell surface.
2003,
Pubmed
Pinto,
Influenza virus M2 protein has ion channel activity.
1992,
Pubmed
,
Xenbase
Pinto,
A functionally defined model for the M2 proton channel of influenza A virus suggests a mechanism for its ion selectivity.
1997,
Pubmed
,
Xenbase
Pinto,
The M2 proton channels of influenza A and B viruses.
2006,
Pubmed
Sakaguchi,
The active oligomeric state of the minimalistic influenza virus M2 ion channel is a tetramer.
1997,
Pubmed
Sauter,
Crystallographic detection of a second ligand binding site in influenza virus hemagglutinin.
1992,
Pubmed
Schnell,
Structure and mechanism of the M2 proton channel of influenza A virus.
2008,
Pubmed
Shuck,
Analysis of the pore structure of the influenza A virus M(2) ion channel by the substituted-cysteine accessibility method.
2000,
Pubmed
,
Xenbase
Stouffer,
Structural basis for the function and inhibition of an influenza virus proton channel.
2008,
Pubmed
Subczynski,
Partitioning and localization of spin-labeled amantadine in lipid bilayers: an EPR study.
1998,
Pubmed
Sugrue,
Structural characteristics of the M2 protein of influenza A viruses: evidence that it forms a tetrameric channel.
1991,
Pubmed
Takeda,
Influenza a virus M2 ion channel activity is essential for efficient replication in tissue culture.
2002,
Pubmed
Tang,
The gate of the influenza virus M2 proton channel is formed by a single tryptophan residue.
2002,
Pubmed
,
Xenbase
Varghese,
Structural evidence for a second sialic acid binding site in avian influenza virus neuraminidases.
1997,
Pubmed
Venkataraman,
Chemical rescue of histidine selectivity filter mutants of the M2 ion channel of influenza A virus.
2005,
Pubmed
,
Xenbase
Wang,
Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block.
1993,
Pubmed
,
Xenbase
Wang,
Amantadine partition and localization in phospholipid membrane: a solution NMR study.
2004,
Pubmed
Zhirnov,
Solubilization of matrix protein M1/M from virions occurs at different pH for orthomyxo- and paramyxoviruses.
1990,
Pubmed
