Structural basis for the function and inhibition of an influenza virus proton channel

Amanda L. Stouffer, Rudresh Acharya, David Salom, Anna S. Levine, Luigi Di Costanzo, Cinque S. Soto, Valentina Tereshko, Vikas Nanda, Steven Stayrook, William F. DeGrado

Research output: Contribution to journalArticlepeer-review

473 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)596-599
Number of pages4
JournalNature
Volume451
Issue number7178
DOIs
StatePublished - Jan 31 2008

All Science Journal Classification (ASJC) codes

  • General

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