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

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(2). The drug- binding site is lined by residues that are mutated in amantadine- resistant viruses(3,4). 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.