ArticleJournal of the American Chemical Society2013
Drug-induced conformational and dynamical changes of the S31N mutant of the influenza M2 proton channel investigated by solid-state NMR.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 72 citations in OpenAlex.
- Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches.RSC medicinal chemistry · 2026Review
- Side Chain Structures of the Proton-Selective Histidine and Gating Tryptophan in Influenza BM2 Reveal Both Conservation and Variation of the Proton Conduction Mechanism.Biochemistry · 2025Article
- Molecular biophysics and inhibition mechanism of influenza virus A M2 viroporin by adamantane-based drugs - Challenges in designing antiviral agents.Journal of structural biology: X · 2025Article
- Solid-State NMR of Virus Membrane Proteins.Accounts of chemical research · 2025Article
- Structure and dynamics of the proton-selective histidine and the gating tryptophan in an inward rectifying hybrid influenza B and A virus M2 proton channel.Physical chemistry chemical physics : PCCP · 2024Article
- Antiviral Approaches against Influenza Virus.Clinical microbiology reviews · 2023Review
- New type of RNA virus replication inhibitor based on decahydro-closo-decaborate anion containing amino acid ester pendant group.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2022Article
- Construction of multi-substituted pyrazolesRSC advances · 2022Article
- The role of structural dynamics in the thermal adaptation of hyperthermophilic enzymes.Frontiers in molecular biosciences · 2022Article
- Influenza AM2 Channel Oligomerization Is Sensitive to Its Chemical Environment.Analytical chemistry · 2021Article
- Virus Structures and Dynamics by Magic-Angle Spinning NMR.Annual review of virology · 2021Review
- Native Chemical Ligation of Highly Hydrophobic Peptides in Ionic Liquid-Containing Media.The Journal of organic chemistry · 2021Article
- Increased Dissociation of Adamantanamines in Influenza A M2 S31N with Partial Block by Rimantadine.Biophysical journal · 2020Article
- Chemical Probes for Blocking of Influenza A M2 Wild-type and S31N Channels.ACS chemical biology · 2020Article
- Investigation of the Drug Resistance Mechanism of M2-S31N Channel Blockers through Biomolecular Simulations and Viral Passage Experiments.ACS pharmacology & translational science · 2020Article
- Discovery of M2 channel blockers targeting the drug-resistant double mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2020Article
- Interplay between membrane curvature and protein conformational equilibrium investigated by solid-state NMR.Journal of structural biology · 2019Article
- Structure and Dynamics of Membrane Proteins from Solid-State NMR.Annual review of biophysics · 2018Review
- Transport-Relevant Protein Conformational Dynamics and Water Dynamics on Multiple Time Scales in an Archetypal Proton Channel: Insights from Solid-State NMR.Journal of the American Chemical Society · 2018Article
- Protonation equilibria and pore-opening structure of the dual-histidine influenza B virus M2 transmembrane proton channel from solid-state NMR.The Journal of biological chemistry · 2017Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The M2 protein of influenza A viruses forms a tetrameric proton channel that is targeted by the amantadine class of antiviral drugs. A S31N mutation in the transmembrane (TM) domain of the protein has caused widespread amantadine resistance in most of the currently circulating flu viruses. Recently, a new family of compounds based on amantadine- and aryl-substituted isoxazole were discovered to inhibit the S31N channel activity and reduce replication of S31N-harboring viruses. We now use solid-state NMR spectroscopy to investigate the effects of one of these isoxazole compounds, WJ352, on the conformation of the S31N TM segment and the dynamics of the proton-selective residue, His37. Chemical shift perturbations show that WJ352 changes the conformational equilibrium of multiple TM residues, with the maximal perturbation occurring at the crucial Asn31. (13)C-(2)H distance measurements and (1)H-(1)H NOE cross peaks indicate that the adamantane moiety of the drug is bound in the spacious pore between Asn31 and Gly34 while the phenyl tail is located near Val27. Thus, the polar amine points to the channel exterior rather than to His37, in contrast to amantadine and rimantadine in the wild-type channel, suggesting that the drug is significantly stabilized by hydrophobic interactions between the adamantane and the TM peptide. (15)N and (13)C chemical shifts indicate that at low pH, His37 undergoes fast exchange among the τ tautomer, the π tautomer, and the cationic state due to proton transfer with water. The exchange rate is higher than the wild-type channel, consistent with the larger single-channel conductance of the mutant. Drug binding at acidic pH largely suppresses this exchange, reverting the histidines to a similar charge distribution as that of the high-pH closed state.
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