2LY0

Solution NMR structure of the influenza A virus S31N mutant (19-49) in presence of drug M2WJ332

2LY0 の概要

• エントリーDOI: 10.2210/pdb2ly0/pdb
• NMR情報: BMRB: 18706
• 分子名称: Membrane ion channel M2, (3S,5S,7S)-N-{[5-(thiophen-2-yl)-1,2-oxazol-3-yl]methyl}tricyclo[3.3.1.1~3,7~]decan-1-aminium (2 entities in total)
• 機能のキーワード: influenza a virus, m2 channel, s31n inhibitor, viral protein
• 由来する生物種: Influenza A virus
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 14303.92

構造登録者

Wu, Y.,Wang, J.,DeGrado, W. (登録日: 2012-09-10, 公開日: 2013-01-09, 最終更新日: 2024-05-15)

主引用文献

Wang, J.,Wu, Y.,Ma, C.,Fiorin, G.,Wang, J.,Pinto, L.H.,Lamb, R.A.,Klein, M.L.,Degrado, W.F.
Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus.
Proc.Natl.Acad.Sci.USA, 110:1315-1320, 2013

PubMed Abstract: The influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine, whose use has been discontinued due to widespread drug resistance. Among the handful of drug-resistant mutants, S31N is found in more than 95% of the currently circulating viruses and shows greatly decreased inhibition by amantadine. The discovery of inhibitors of S31N has been hampered by the limited size, polarity, and dynamic nature of its amantadine-binding site. Nevertheless, we have discovered small-molecule drugs that inhibit S31N with potencies greater than amantadine's potency against WT M2. Drug binding locks the protein into a well-defined conformation, and the NMR structure of the complex shows the drug bound in the homotetrameric channel, threaded between the side chains of Asn31. Unrestrained molecular dynamics simulations predicted the same binding site. This S31N inhibitor, like other potent M2 inhibitors, contains a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These sites might stabilize hydronium-like species formed as protons diffuse through the outer channel to the proton-shuttling residue His37 near the cytoplasmic end of the channel.

PubMed: 23302696
DOI: 10.1073/pnas.1216526110

実験手法

SOLUTION NMR