title: Crystal structure of the drug-resistant S31N influenza M2 proton channel.
abstract: The M2 protein is a small proton channel found in the influenza A virus that is necessary for viral replication. The M2 channel is the target of a class of drugs called the adamantanes, which block the channel pore and prevent the virus from replicating. In recent decades mutations have arisen in M2 that prevent the adamantanes from binding to the channel pore, with the most prevalent of these mutations being S31N. Here we report the first crystal structure of the S31N mutant crystallized using lipidic cubic phase crystallization techniques and solved to 1.59 Å resolution. The Asn31 residues point directly into the center of the channel pore and form a hydrogen-bonded network that disrupts the drug-binding site. Ordered waters in the channel pore form a continuous hydrogen bonding network from Gly34 to His37.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, 555 Mission Bay Blvd. (S) Room 452V, San Francisco, California, 94158.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Thomaston
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, 555 Mission Bay Blvd. (S) Room 452V, San Francisco, California, 94158.
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
mesh_terms: D000547:Amantadine / Q000031:analogs & derivatives / Q000737:chemistry; D000998:Antiviral Agents / Q000737:chemistry; D001216:Asparagine / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000235:genetics*; D015870:Gene Expression; D006860:Hydrogen Bonding; D009980:Influenza A virus / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011522:Protons; D012694:Serine / Q000737:chemistry*; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D001216:Asparagine; D011522:Protons; D012694:Serine; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C005660:adamantanine
keywords: S31N; crystal structure; influenza M2; proton channel