Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers

Sarah D. Cady, Klaus Schmidt-Rohr, Jun Wang, Cinque S. Soto, William F. DeGrado and Mei Hong ()
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Sarah D. Cady: Iowa State University, Ames, Iowa 50011 2, USA
Klaus Schmidt-Rohr: Iowa State University, Ames, Iowa 50011 2, USA
Jun Wang: School of Medicine, Philadelphia, Pennsylvania 19104-6059, USA
Cinque S. Soto: School of Medicine, Philadelphia, Pennsylvania 19104-6059, USA
William F. DeGrado: School of Medicine, Philadelphia, Pennsylvania 19104-6059, USA
Mei Hong: Iowa State University, Ames, Iowa 50011 2, USA

Nature, 2010, vol. 463, issue 7281, 689-692

Abstract: Double life of flu virus protein The current H1N1 strain pandemic virus is resistant to the established antiviral agents amantadine and rimantadine, which target the M2 protein, a multifunctional membrane-spanning proton channel. The structure of this channel has been a subject of some controversy, since an X-ray crystal structure of part of the M2 channel showed electron density that corresponded to a single molecule of amantadine in the N-terminal half of the pore, whereas a solution NMR structure of a larger portion of the channel showed four rimantadine molecules bound to the C-terminal lipid-facing surface of the helices. The matter now appears resolved with the publication of the high-resolution structure of the M2 channel in a phospholipid bilayer, determined using solid-state NMR spectroscopy. This reveals two amantadine-binding sites: a high-affinity site in the N-terminal channel lumen and a low-affinity site on the C-terminal protein surface. This work could be of value for the development of new anti-influenza drugs, an important goal since the 2009 seasonal virus is amantadine-sensitive but resistant to Tamiflu, raising the possibility that multiply resistant virus types might emerge in future.

Date: 2010
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DOI: 10.1038/nature08722

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