tetano
Editor, Senior Moderator
Structure. 2011 Nov 9;19(11):1655-63.
Structural Investigation of Rimantadine Inhibition of the AM2-BM2 Chimera Channel of Influenza Viruses.
Pielak RM, Oxenoid K, Chou JJ.
Source
Jack and Eileen Connors Structural Biology Laboratory, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID:
22078564
[PubMed - in process]
http://www.ncbi.nlm.nih.gov/pubmed/22078564
Structural Investigation of Rimantadine Inhibition of the AM2-BM2 Chimera Channel of Influenza Viruses.
Pielak RM, Oxenoid K, Chou JJ.
Source
Jack and Eileen Connors Structural Biology Laboratory, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID:
22078564
[PubMed - in process]
http://www.ncbi.nlm.nih.gov/pubmed/22078564