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J Am Chem Soc. 2019 Jul 24;141(29):11481-11488. doi: 10.1021/jacs.9b02196. Epub 2019 Jul 11.

X-ray Crystal Structure of the Influenza A M2 Proton Channel S31N Mutant in Two Conformational States: An Open and Shut Case.

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Department of Pharmaceutical Chemistry , University of California , San Francisco , California 94158 , United States.
State Key Laboratory of Chemical Oncogenomics , Peking University Shenzhen Graduate School , Shenzhen 518055 , China.
DLX Scientific , Lawrence , Kansas 66049 , United States.
Department of Pharmacology and Toxicology, College of Pharmacy , University of Arizona , Tucson , Arizona 85721 , United States.


The amantadine-resistant S31N mutant of the influenza A M2 proton channel has become prevalent in currently circulating viruses. Here, we have solved an X-ray crystal structure of M2(22-46) S31N that contains two distinct conformational states within its asymmetric unit. This structure reveals the mechanism of adamantane resistance in both conformational states of the M2 channel. In the Inwardopen conformation, the mutant Asn31 side chain faces the channel pore and sterically blocks the adamantane binding site. In the Inwardclosed conformation, Asn31 forms hydrogen bonds with carbonyls at the monomer-monomer interface, which twists the monomer helices and constricts the channel pore at the drug binding site. We also examine M2(19-49) WT and S31N using solution NMR spectroscopy and show that distribution of the two conformational states is dependent on both detergent choice and experimental pH.


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