tetano
Editor, Senior Moderator
J Med Chem. 2017 Jan 20. doi: 10.1021/acs.jmedchem.6b01115. [Epub ahead of print]
[h=1]Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained.[/h] Tzitzoglaki C, Wright AK, Freudenberger KM, Hoffmann A, Tietjen I, Stylianakis I, Kolarov F, Fedida D, Schmidtke M, Gauglitz G, Cross TA, Kolocouris A.
[h=3]Abstract[/h] While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2S31N are unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, anti-viral assays and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WT compared to negligible or weak binding to M2S31N. This is due to reshaping of the M2pore when N31 is present, which in contrast to 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-terminal helical domain relative to the bilayer normal includes the W41 primary gate for proton conductance and may prevent the gate from opening, representing an alternative view for how these drugs prevent proton conductance.
PMID: 28107633 DOI: 10.1021/acs.jmedchem.6b01115
[PubMed - as supplied by publisher]
[h=1]Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained.[/h] Tzitzoglaki C, Wright AK, Freudenberger KM, Hoffmann A, Tietjen I, Stylianakis I, Kolarov F, Fedida D, Schmidtke M, Gauglitz G, Cross TA, Kolocouris A.
[h=3]Abstract[/h] While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2S31N are unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, anti-viral assays and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WT compared to negligible or weak binding to M2S31N. This is due to reshaping of the M2pore when N31 is present, which in contrast to 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-terminal helical domain relative to the bilayer normal includes the W41 primary gate for proton conductance and may prevent the gate from opening, representing an alternative view for how these drugs prevent proton conductance.
PMID: 28107633 DOI: 10.1021/acs.jmedchem.6b01115
[PubMed - as supplied by publisher]