title: Structural investigation of rimantadine inhibition of the AM2-BM2 chimera channel of influenza viruses.
abstract: The M2 channel of influenza A is a target of the adamantane family antiviral drugs. Two different drug-binding sites have been reported: one inside the pore, and the other is a lipid-facing pocket. A previous study showed that a chimera of M2 variants from influenza A and B that contains only the pore-binding site is sensitive to amantadine inhibition, suggesting that the primary site of inhibition is inside the pore. To obtain atomic details of channel-drug interaction, we determined the structures of the chimeric channel with and without rimantadine. Inside the channel and near the N-terminal end, methyl groups of Val27 and Ala30 from four subunits form a hydrophobic pocket around the adamantane, and the drug amino group appears to be in polar contact with the backbone oxygen of Ala30. The structures also reveal differences between the drug-bound and -unbound states of the channel that can explain drug resistance.
authors.affiliation: Jack and Eileen Connors Structural Biology Laboratory, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Pielak
authors.forename: Kirill
authors.initials: K
authors.lastname: Oxenoid
authors.forename: James J
authors.initials: JJ
authors.lastname: Chou
mesh_terms: D020816:Amino Acid Motifs; D000998:Antiviral Agents / Q000737:chemistry*; D001665:Binding Sites; D009980:Influenza A virus; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D012299:Rimantadine / Q000737:chemistry*; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D000086082:Viroporin Proteins
chemical_list: D000998:Antiviral Agents; D008081:Liposomes; D012299:Rimantadine; D014760:Viral Fusion Proteins; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
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