title: Structural basis for the function and inhibition of an influenza virus proton channel.
abstract: The M2 protein from influenza A virus is a pH-activated proton channel that mediates acidification of the interior of viral particles entrapped in endosomes. M2 is the target of the anti-influenza drugs amantadine and rimantadine; recently, resistance to these drugs in humans, birds and pigs has reached more than 90% (ref. 1). Here we describe the crystal structure of the transmembrane-spanning region of the homotetrameric protein in the presence and absence of the channel-blocking drug amantadine. pH-dependent structural changes occur near a set of conserved His and Trp residues that are involved in proton gating. The drug-binding site is lined by residues that are mutated in amantadine-resistant viruses. Binding of amantadine physically occludes the pore, and might also perturb the pK(a) of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2-channel blockers.
authors.affiliation: Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Stouffer
authors.forename: Rudresh
authors.initials: R
authors.lastname: Acharya
authors.forename: David
authors.initials: D
authors.lastname: Salom
authors.forename: Anna S
authors.initials: AS
authors.lastname: Levine
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Costanzo
authors.forename: Cinque S
authors.initials: CS
authors.lastname: Soto
authors.forename: Valentina
authors.initials: V
authors.lastname: Tereshko
authors.forename: Vikas
authors.initials: V
authors.lastname: Nanda
authors.forename: Steven
authors.initials: S
authors.lastname: Stayrook
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
mesh_terms: D000547:Amantadine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000235:genetics; D006639:Histidine / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D009980:Influenza A virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D011522:Protons; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D006639:Histidine; D011522:Protons; D014364:Tryptophan; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins