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Medicinal-Pharmaceutical Chemistry Commons

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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Membrane-Dependent Effects Of A Cytoplasmic Helix On The Structure And Drug Binding Of The Influenza Virus M2 Protein, Sarah D. Cady, Tuo Wang, Mei Hong Jun 2011

Membrane-Dependent Effects Of A Cytoplasmic Helix On The Structure And Drug Binding Of The Influenza Virus M2 Protein, Sarah D. Cady, Tuo Wang, Mei Hong

Chemistry Publications

The influenza A M2 protein forms a proton channel for virus infection and also mediates virus assembly and budding. The minimum protein length that encodes both functions contains the transmembrane (TM) domain (roughly residues 22ā€“46) for the amantadine-sensitive proton-channel activity and an amphipathic cytoplasmic helix (roughly residues 45ā€“62) for curvature induction and virus budding. However, structural studies involving the TM domain with or without the amphipathic helix differed on the drug-binding site. Here we use solid-state NMR spectroscopy to determine the amantadine binding site in the cytoplasmic-helix-containing M2(21ā€“61). 13Cā€“2H distance measurements of 13C-labeled protein and ...


Specific Binding Of Adamantane Drugs And Direction Of Their Polar Amines In The Pore Of The Influenza M2 Transmembrane Domain In Lipid Bilayers And Dodecylphosphocholine Micelles Determined By Nmr Spectroscopy, Sarah D. Cady, Jun Wang, Yibing Wu, William F. Degrado, Mei Hong Mar 2011

Specific Binding Of Adamantane Drugs And Direction Of Their Polar Amines In The Pore Of The Influenza M2 Transmembrane Domain In Lipid Bilayers And Dodecylphosphocholine Micelles Determined By Nmr Spectroscopy, Sarah D. Cady, Jun Wang, Yibing Wu, William F. Degrado, Mei Hong

Chemistry Publications

The transmembrane domain of the influenza M2 protein (M2TM) forms a tetrameric proton channel important for the virus lifecycle. The proton-channel activity is inhibited by amine-containing adamantyl drugs amantadine and rimantadine, which have been shown to bind specifically to the pore of M2TM near Ser31. However, whether the polar amine points to the N- or C-terminus of the channel has not yet been determined. Elucidating the polar group direction will shed light on the mechanism by which drug binding inhibits this proton channel and will facilitate rational design of new inhibitors. In this study, we determine the polar amine direction ...


Conformational Plasticity Of The Influenza A M2 Transmembrane Helix In Lipid Bilayers Under Varying Ph, Drug Binding, And Membrane Thickness, Fanghao Hu, Wenbin Luo, Sarah D. Cady, Mei Hong Jan 2011

Conformational Plasticity Of The Influenza A M2 Transmembrane Helix In Lipid Bilayers Under Varying Ph, Drug Binding, And Membrane Thickness, Fanghao Hu, Wenbin Luo, Sarah D. Cady, Mei Hong

Chemistry Publications

Membrane proteins change their conformations to respond to environmental cues, thus conformational plasticity is important for function. The influenza A M2 protein forms an acid-activated proton channel important for the virus lifecycle. Here we have used solid-state NMR spectroscopy to examine the conformational plasticity of membrane-bound transmembrane domain of M2 (M2TM). 13C and 15N chemical shifts indicate coupled conformational changes of several pore-facing residues due to changes in bilayer thickness, drug binding, and pH. The structural changes are attributed to the formation of a well-defined helical kink at G34 in the drug-bound state and in thick lipid bilayers, nonideal backbone ...