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

Amanda L Stouffer1, Rudresh Acharya, David Salom

  • 1Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Nature
|February 1, 2008
PubMed

Insights

The influenza A virus M2 protein structure reveals how amantadine blocks proton flow. Understanding this mechanism is crucial for developing new drugs against widespread drug-resistant influenza strains.

Area of Science:

  • Structural biology
  • Virology
  • Drug discovery

Background:

  • Influenza A virus M2 protein functions as a pH-activated proton channel.
  • Amantadine and rimantadine are anti-influenza drugs targeting the M2 channel.
  • Widespread resistance (>90%) to amantadine and rimantadine necessitates new therapeutic strategies.

Purpose of the Study:

  • To determine the crystal structure of the M2 protein's transmembrane region.
  • To elucidate the structural basis of amantadine's interaction with the M2 channel.
  • To provide insights into the mechanisms of amantadine resistance.

Main Methods:

  • X-ray crystallography was used to obtain the structure of the M2 protein's transmembrane domain.
  • Structures were determined in the presence and absence of the drug amantadine.
  • Analysis of conserved residues and drug-binding sites was performed.

Main Results:

  • The crystal structure of the homotetrameric M2 protein transmembrane region was solved.
  • pH-dependent structural changes involving conserved His and Trp residues were identified.
  • The amantadine-binding site was characterized, revealing its occlusion of the proton pore.
  • Mutations conferring amantadine resistance were found to line the drug-binding site.

Conclusions:

  • The determined structure provides a molecular basis for amantadine's channel-blocking activity.
  • Structural insights explain how amantadine resistance mutations affect drug binding.
  • This structural information serves as a foundation for designing new M2 channel blockers to overcome drug resistance.

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