Open AccessBinding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained
Author(s) -
Christina Tzitzoglaki,
Anna K. Wright,
Kathrin Freudenberger,
Anja Hoffmann,
Ian Tietjen,
Ioannis Papanastasiou,
Felix Kolarov,
David Fedida,
Michaela Schmidtke,
Günter Gauglitz,
Timothy A. Cross,
Antonios Kolocouris
Publication year - 2017
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.6b01115
Subject(s) - chemistry , isothermal titration calorimetry , proton , crystallography , conductance , molecular dynamics , ligand (biochemistry) , stereochemistry , biophysics , computational chemistry , biochemistry , receptor , physics , mathematics , quantum mechanics , combinatorics , biology
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-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.