Referenced in: none

Automatically associated channels: Kir6.2

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

Authors: 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

Journal, date & volume: Nature, 2008 Jan 31 , 451, 596-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18235504

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.