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Backbone Structure of the Amantadine-Blocked Trans-Membrane Domain M2 Proton Channel from Influenza A Virus

Jun Hu ^*, Tom Asbury , Srisairam Achuthan  , Conggang Li  ^¶, Richard Bertram  , Jack R. Quine   ^¶, Riqiang Fu ^¶ and Timothy A. Cross   ^¶

^* The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; Institute of Molecular Biophysics, Department of Mathematics, Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida; and ^¶ National High Magnetic Field Laboratory, Tallahassee, Florida

Correspondence: Address reprint requests to T. A. Cross, Tel.: 850-644-0917; E-mail: cross{at}magnet.fsu.edu.

Amantadine is known to block the M2 proton channel of the Influenza A virus. Here, we present a structure of the M2 trans-membrane domain blocked with amantadine, built using orientational constraints obtained from solid-state NMR polarization-inversion-spin-exchange-at-the-magic-angle experiments. The data indicates a kink in the monomer between two helical fragments having 20° and 31° tilt angles with respect to the membrane normal. This monomer structure is then used to construct a plausible model of the tetrameric amantadine-blocked M2 trans-membrane channel. The influence of amantadine binding through comparative cross polarization magic-angle spinning spectra was also observed. In addition, spectra are shown of the amantadine-resistant mutant, S31N, in the presence and absence of amantadine.

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