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(08-0529) Dr. Jason Schnell, Harvard Medical School

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Dr. Jason Schnell, Harvard Medical School

The M2 Proton Channel from Influenza A: Structure, Mechanism and Drug Inhibition

The integral membrane protein M2 from the influenza virus is a pH-activated proton channel required for (i) uncoating the viral ribonucleoprotein complex, and (ii) preventing premature conversion of newly synthesized hemagglutinin to the fusion active form. The adamantanes are an inexpensive and widely-used class of drugs, which treat influenza infection by inhibiting M2. In recent years, resistance to the adamantanes has become widespread both in the seasonal influenza strains common in the U.S., and in the Asiatic avian influenza strains. Understanding the mechanism of M2 inhibition by the adamantanes and the compensating action of drug-resistant mutations has been hindered by the lack of atomic-level structural information. We have solved the high-resolution structure of the tetrameric M2 channel domain in the inactivated, rimantadine-bound state by solution NMR. The structure reveals a channel gate locking mechanism in which the closed conformation of the tryptophan gate is stabilized by an intermolecular hydrogen bond. This finding, along with direct measurement of channel gate dynamics as a function of pH, support a model in which channel activation is intimately linked to channel domain assembly. Rimantadine binds to and stabilizes the channel gate from the lipid bilayer -- rather than at the channel pore -- consistent with the high membrane-partitioning of this class of hydrophobic drugs. Inspection of resistance-conferring mutations in the context of the high-resolution structure suggests that the mutations act by either destabilizing channel assembly, or making the channel pore more hydrophilic, both of which would make the channel easier open. Functional and biophysical experiments on adamantane-resistant M2 mutants are now being performed to test this model.

For more information contact Prof. Wendy Kelly (404-385-1154).

Status

  • Workflow Status:Published
  • Created By:Shirley Tomes
  • Created:05/19/2008
  • Modified By:Fletcher Moore
  • Modified:10/07/2016

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