title: Binding and Proton Blockage by Amantadine Variants of the Influenza M2WTand M2S31NExplained.
abstract: While aminoadamantanes are well-established inhibitors of the influenza A M2 proton channel, the mechanisms by which they are rendered ineffective against M2S31Nare unclear. Solid state NMR, isothermal titration calorimetry, electrophysiology, antiviral assays, and molecular dynamics simulations suggest stronger binding interactions for aminoadamantanes to M2WTcompared to negligible or weak binding to M2S31N. 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.
authors.affiliation: Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens , Athens 157 71, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Tzitzoglaki
authors.affiliation: Institute of Molecular Biophysics and National High Magnetic Field Laboratory, Florida State University , Tallahassee, Florida 32306, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Wright
authors.affiliation: Institut für Physikalische und Theoretische Chemie, Eberhard-Karls Universität , Auf der Morgenstelle 18, D-72076 Tübingen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Freudenberger
authors.affiliation: Department of Virology and Antiviral Therapy, Jena University Hospital , Hans Knoell Strasse 2, D-07745 Jena, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia , Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Tietjen
authors.affiliation: Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens , Athens 157 71, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Stylianakis
authors.affiliation: Institut für Physikalische und Theoretische Chemie, Eberhard-Karls Universität , Auf der Morgenstelle 18, D-72076 Tübingen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Kolarov
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia , Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Fedida
authors.affiliation: Department of Virology and Antiviral Therapy, Jena University Hospital , Hans Knoell Strasse 2, D-07745 Jena, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schmidtke
authors.affiliation: Institut für Physikalische und Theoretische Chemie, Eberhard-Karls Universität , Auf der Morgenstelle 18, D-72076 Tübingen, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Gauglitz
authors.affiliation: Institute of Molecular Biophysics and National High Magnetic Field Laboratory, Florida State University , Tallahassee, Florida 32306, United States.|Department of Chemistry and Biochemistry, Florida State University , Tallahassee, Florida 32306, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Cross
authors.affiliation: Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens , Athens 157 71, Greece.
authors.forename: Antonios
authors.identifier: 0000-0001-6110-1903
authors.initials: A
authors.lastname: Kolocouris
mesh_terms: D000547:Amantadine / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D009980:Influenza A virus / Q000187:drug effects*; D008024:Ligands; D011522:Protons; D013057:Spectrum Analysis; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D008024:Ligands; D011522:Protons; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins