Binding and Proton Blockage by Amantadine Variants of the Influenza M2WT and M2S31N Explained
| Autor: | Timothy A. Cross, Kathrin Freudenberger, Antonios Kolocouris, Anja Hoffmann, Ioannis Stylianakis, Ian Tietjen, Felix Kolarov, Anna K. Wright, David Fedida, Christina Tzitzoglaki, Günter Gauglitz, Michaela Schmidtke |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Proton Ligands 010402 general chemistry Antiviral Agents 01 natural sciences Article Viral Matrix Proteins 03 medical and health sciences Molecular dynamics Drug Discovery Amantadine biology Chemistry Spectrum Analysis Bilayer Conductance Isothermal titration calorimetry Ligand (biochemistry) 0104 chemical sciences Crystallography 030104 developmental biology Solid-state nuclear magnetic resonance M2 proton channel Influenza A virus biology.protein Molecular Medicine Protons |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b01115 |
| Popis: | 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 amino adamantanes 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. |
| Databáze: | OpenAIRE |
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