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Amantadine

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Timothy A. Cross – 1st expert on this subject based on the ideXlab platform

  • backbone structure of the Amantadine blocked trans membrane domain m2 proton channel from influenza a virus
    Biophysical Journal, 2007
    Co-Authors: Jun Hu, T. Asbury, Srisairam Achuthan, Conggang Li, Jack R. Quine, Riqiang Fu, Richard Bertram, Timothy A. Cross

    Abstract:

    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.

  • Backbone structure of the Amantadine-blocked trans-membrane domain M2 proton channel from influenza A virus
    Biophysical Journal, 2007
    Co-Authors: Jun Hu, T. Asbury, Srisairam Achuthan, Conggang Li, Rachael Bertram, Jack R. Quine, Riqiang Fu, Timothy A. Cross

    Abstract:

    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. © 2007 by the Biophysical Society.

Jun Hu – 2nd expert on this subject based on the ideXlab platform

  • backbone structure of the Amantadine blocked trans membrane domain m2 proton channel from influenza a virus
    Biophysical Journal, 2007
    Co-Authors: Jun Hu, T. Asbury, Srisairam Achuthan, Conggang Li, Jack R. Quine, Riqiang Fu, Richard Bertram, Timothy A. Cross

    Abstract:

    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.

  • Backbone structure of the Amantadine-blocked trans-membrane domain M2 proton channel from influenza A virus
    Biophysical Journal, 2007
    Co-Authors: Jun Hu, T. Asbury, Srisairam Achuthan, Conggang Li, Rachael Bertram, Jack R. Quine, Riqiang Fu, Timothy A. Cross

    Abstract:

    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. © 2007 by the Biophysical Society.

Mei Hong – 3rd expert on this subject based on the ideXlab platform

  • Amantadine induced conformational and dynamical changes of the influenza m2 transmembrane proton channel
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Sarah D Cady, Mei Hong

    Abstract:

    The M2 protein of influenza A virus forms a transmembrane proton channel important for viral infection and replication. Amantadine blocks this channel, thus inhibiting viral replication. Elucidating the high-resolution structure of the M2 protein and its change upon Amantadine binding is crucial for designing antiviral drugs to combat the growing resistance of influenza A viruses against Amantadine. We used magic-angle-spinning solid-state NMR to determine the conformation and dynamics of the transmembrane domain of the protein M2TMP in the apo- and Amantadine-bound states in lipid bilayers. 13C chemical shifts and torsion angles of the protein in 1,2-dilauroyl-sn-glycero-3-phosphatidylcholine (DLPC) bilayers indicate that M2TMP is α-helical in both states, but the average conformation differs subtly, especially at the G34–I35 linkage and V27 side chain. In the liquid-crystalline membrane, the complexed M2TMP shows dramatically narrower lines than the apo peptide. Analysis of the homogeneous and inhomogeneous line widths indicates that the apo-M2TMP undergoes significant microsecond-time scale motion, and Amantadine binding alters the motional rates, causing line-narrowing. Amantadine also reduces the conformational heterogeneity of specific residues, including the G34/I35 pair and several side chains. Finally, Amantadine causes the helical segment N-terminal to G34 to increase its tilt angle by 3°, and the G34–I35 torsion angles cause a kink of 5° in the Amantadine-bound helix. These data indicate that Amantadine affects the M2 proton channel mainly by changing the distribution and exchange rates among multiple low-energy conformations and only subtly alters the average conformation and orientation. Amantadine-resistant mutations thus may arise from binding-incompetent changes in the conformational equilibrium.

  • Amantadine-induced conformational and dynamical changes of the influenza M2 transmembrane proton channel.
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Sarah D Cady, Mei Hong

    Abstract:

    The M2 protein of influenza A virus forms a transmembrane proton channel important for viral infection and replication. Amantadine blocks this channel, thus inhibiting viral replication. Elucidating the high-resolution structure of the M2 protein and its change upon Amantadine binding is crucial for designing antiviral drugs to combat the growing resistance of influenza A viruses against Amantadine. We used magic-angle-spinning solid-state NMR to determine the conformation and dynamics of the transmembrane domain of the protein M2TMP in the apo- and Amantadine-bound states in lipid bilayers. (13)C chemical shifts and torsion angles of the protein in 1,2-dilauroyl-sn-glycero-3-phosphatidylcholine (DLPC) bilayers indicate that M2TMP is alpha-helical in both states, but the average conformation differs subtly, especially at the G34-I35 linkage and V27 side chain. In the liquid-crystalline membrane, the complexed M2TMP shows dramatically narrower lines than the apo peptide. Analysis of the homogeneous and inhomogeneous line widths indicates that the apo-M2TMP undergoes significant microsecond-time scale motion, and Amantadine binding alters the motional rates, causing line-narrowing. Amantadine also reduces the conformational heterogeneity of specific residues, including the G34/I35 pair and several side chains. Finally, Amantadine causes the helical segment N-terminal to G34 to increase its tilt angle by 3 degrees , and the G34-I35 torsion angles cause a kink of 5 degrees in the Amantadine-bound helix. These data indicate that Amantadine affects the M2 proton channel mainly by changing the distribution and exchange rates among multiple low-energy conformations and only subtly alters the average conformation and orientation. Amantadine-resistant mutations thus may arise from binding-incompetent changes in the conformational equilibrium.