Protonation of Histidine and Histidine−Tryptophan Interaction in the Activation of the M2 Ion Channel from Influenza A Virus†

Biochemistry ◽  
2001 ◽  
Vol 40 (20) ◽  
pp. 6053-6060 ◽  
Author(s):  
Atsushi Okada ◽  
Takashi Miura ◽  
Hideo Takeuchi
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A

Direct Measurement of the Influenza A Virus M2 Protein Ion Channel Activity in Mammalian Cells

Virology ◽  
1994 ◽  
Vol 205 (1) ◽  
pp. 133-140 ◽  
Author(s):  
Chang Wang ◽  
Robert A. Lamb ◽  
Lawrence H. Pinto
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Direct Measurement ◽  
Mammalian Cells ◽  
Influenza A ◽  
Channel Activity ◽  
M2 Protein

scholarly journals Activation mechanism of the M2 ion channel of influenza A virus

2000 ◽  
Vol 40 (supplement) ◽  
pp. S32
Author(s):  
A. Okada ◽  
T. Miura ◽  
H. Takeuchi
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Activation Mechanism

scholarly journals Effect of Cytoplasmic Tail Truncations on the Activity of the M2 Ion Channel of Influenza A Virus

1999 ◽  
Vol 73 (12) ◽  
pp. 9695-9701 ◽  
Author(s):  
Kurt Tobler ◽  
Marie L. Kelly ◽  
Lawrence H. Pinto ◽  
Robert A. Lamb
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Transmembrane Domain ◽  
Stop Codon ◽  
Specific Inhibitor ◽  
Cytoplasmic Tail ◽  
Proton Channel ◽  
Tail Region

ABSTRACT The M2 protein of influenza A virus forms a proton channel that is required for viral replication. The M2 ion channel is a homotetramer and has a 24-residue N-terminal extracellular domain, a 19-residue transmembrane domain, and a 54-residue cytoplasmic tail. We show here that the N-terminal methionine residue is cleaved from the mature protein. Translational stop codons were introduced into the M2 cDNA at residues 46, 52, 62, 72, 77, 82, 87, and 92. The deletion mutants were designated truncx, according to the amino acid position that was changed to a stop codon. We studied the role of the cytoplasmic tail by measuring the ion channel activity (the current sensitive to the M2-specific inhibitor amantadine) of the cytoplasmic tail truncation mutants expressed in oocytes of Xenopus laevis. When their conductance was measured over time, mutants trunc72, trunc77, and trunc92 behaved comparably to wild-type M2 protein (a decrease of only 4% over 30 min). In contrast, conductance decreased by 28% for trunc82, 27% for trunc62, and 81% for trunc52 channels. Complete closure of the channel could be observed in some cells for trunc62 and trunc52 within 30 min. These data suggest that a role of the cytoplasmic tail region of the M2 ion channel is to stabilize the pore against premature closure while the ectodomain is exposed to low pH.

scholarly journals Virtual Screening Identifies Chebulagic Acid as an Inhibitor of the M2(S31N) Viral Ion Channel and Influenza A Virus

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2903
Author(s):  
Maggie C. Duncan ◽  
Pascal Amoa Onguéné ◽  
Ibuki Kihara ◽  
Derrick N. Nebangwa ◽  
Maya E. Naidu ◽  
...  
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Viruses ◽  
Drug Resistant ◽  
M2 Protein ◽  
Virtual Screen ◽  
Chebulagic Acid ◽  
Virus Strains

The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antiviral countermeasures. The M2 protein of influenza A is a proton-gated, proton-selective ion channel, which is essential for influenza replication and an established antiviral target. However, all currently circulating influenza A virus strains are now resistant to licensed M2-targeting adamantane drugs, primarily due to the widespread prevalence of an M2 variant encoding a serine to asparagine 31 mutation (S31N). To identify new chemical leads that may target M2(S31N), we performed a virtual screen of molecules from two natural product libraries and identified chebulagic acid as a candidate M2(S31N) inhibitor and influenza antiviral. Chebulagic acid selectively restores growth of M2(S31N)-expressing yeast. Molecular modeling also suggests that chebulagic acid hydrolysis fragments preferentially interact with the highly-conserved histidine residue within the pore of M2(S31N) but not adamantane-sensitive M2(S31). In contrast, chebulagic acid inhibits in vitro influenza A replication regardless of M2 sequence, suggesting that it also acts on other influenza targets. Taken together, results implicate chebulagic acid and/or its hydrolysis fragments as new chemical leads for M2(S31N) and influenza-directed antiviral development.

scholarly journals Identification of the functional core of the influenza A virus A/M2 proton-selective ion channel

2009 ◽  
Vol 106 (30) ◽  
pp. 12283-12288 ◽  
Author(s):  
C. Ma ◽  
A. L. Polishchuk ◽  
Y. Ohigashi ◽  
A. L. Stouffer ◽  
A. Schon ◽  
...  
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A

Identification of camphor derivatives as novel M2 ion channel inhibitors of influenza A virus

MedChemComm ◽  
2015 ◽  
Vol 6 (4) ◽  
pp. 727-731 ◽  
Author(s):  
Xin Zhao ◽  
Zhen-Wei Zhang ◽  
Wei Cui ◽  
Shengwei Chen ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Camphor Derivatives ◽  
Ion Channel Inhibitors

Amantadine derivatives have been the only drugs marketed as M2 inhibitors of influenza A for decades.

scholarly journals Functional Studies and Modeling of Pore-Lining Residue Mutants of the Influenza A Virus M2 Ion Channel

Biochemistry ◽  
2010 ◽  
Vol 49 (4) ◽  
pp. 696-708 ◽  
Author(s):  
Victoria Balannik ◽  
Vincenzo Carnevale ◽  
Giacomo Fiorin ◽  
Benjamin G. Levine ◽  
Robert A. Lamb ◽  
...  
Keyword(s):  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Functional Studies ◽  
Pore Lining

scholarly journals Generation of recombinant influenza A virus without M2 ion-channel protein by introduction of a point mutation at the 5′ end of the viral intron

2005 ◽  
Vol 86 (5) ◽  
pp. 1447-1454 ◽  
Author(s):  
T. K. W. Cheung ◽  
Y. Guan ◽  
S. S. F. Ng ◽  
H. Chen ◽  
C. H. K. Wong ◽  
...  
Keyword(s):  
Cell Culture ◽  
Ion Channel ◽  
Influenza A Virus ◽  
Influenza A ◽  
Gene Mutations ◽  
M2 Protein ◽  
M Gene ◽  
Recombinant Viruses ◽  
Channel Protein ◽  
Splicing Site

The aim of this study was to inhibit influenza virus M2 protein expression by mutating the splicing signal of the M gene. Mutations were introduced into the GU dinucleotide sequence at the 5′-proximal splicing site of the M gene (corresponding to nt 52–53 of M cRNA). Transfected cells expressing mutated M viral ribonucleoproteins failed to generate M2 mRNA. Interestingly, recombinant viruses with mutations at the dinucleotide sequence were viable, albeit attenuated, in cell culture. These recombinants failed to express M2 mRNA and M2 protein. These observations demonstrated that the GU invariant dinucleotide sequence at the 5′-proximal splicing site of M gene is essential for M2 mRNA synthesis. These results also indicated that the M2 ion-channel protein is critical, but not essential, for virus replication in cell culture. This approach may provide a new way of producing attenuated influenza A virus.

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