Binding and Proton Blockage by Amantadine Variants of the Influenza M2_WT and M2_S31N Explained.

ABSTRACT: While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2_S31N are unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, antiviral assays, and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2_WT compared to negligible or weak binding to M2_S31N. This is due to reshaping of the M2 pore when N31 is present, which, in contrast to wild-type (WT), leads (A) to the loss of the V27 pocket for the adamantyl cage and to a predominant orientation of the ligand's ammonium group toward the N-terminus and (B) to the lack of a helical kink upon ligand binding. The kink, which reduces the tilt of the C-ter

SUBMITTER: Tzitzoglaki C 

PROVIDER: S-EPMC9308172 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature