Structural Basis for the Function and Inhibition of an Influenza Virus Proton Channel

Nature. 2008 Jan 31;451(7178):596-9. doi: 10.1038/nature06528.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amantadine / chemistry
  • Amantadine / metabolism
  • Amantadine / pharmacology
  • Crystallography, X-Ray
  • Drug Resistance, Viral / genetics
  • Histidine / metabolism
  • Hydrogen-Ion Concentration
  • Influenza A virus / chemistry*
  • Influenza A virus / genetics
  • Influenza A virus / metabolism
  • Ion Channel Gating / drug effects
  • Models, Molecular
  • Protein Structure, Quaternary
  • Protons
  • Structure-Activity Relationship
  • Tryptophan / metabolism
  • Viral Matrix Proteins / antagonists & inhibitors*
  • Viral Matrix Proteins / chemistry*
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism

Substances

  • M2 protein, Influenza A virus
  • Protons
  • Viral Matrix Proteins
  • Histidine
  • Tryptophan
  • Amantadine

Associated data

  • PDB/3BKD
  • PDB/3C9J