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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.

SUBMITTER: Pielak RM

PROVIDER: S-EPMC5142205 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Structural investigation of rimantadine inhibition of the AM2-BM2 chimera channel of influenza viruses.

Pielak Rafal M RM Oxenoid Kirill K Chou James J JJ

Structure (London, England : 1993) 20111101 11

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 struct ...[more]

PMID: 22078564

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