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

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Bibliographic Details
Title:	Structural basis for the function and inhibition of an influenza virus proton channel.
Authors:	Stouffer, Amanda L., Acharya, Rudresh, Salom, David, Levine, Anna S., Di Costanzo, Luigi, Soto, Cinque S., Tereshko, Valentina, Nanda, Vikas, Stayrook, Steven, DeGrado, William F.
Source:	Nature. 1/31/2008, Vol. 451 Issue 7178, p596-599. 4p. 4 Diagrams.
Subjects:	Influenza A virus, Protons, Acidification, Endosomes, Amantadine, Protein binding, Antibiotic residues
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 pKa of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2-channel blockers. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
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 pKa of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2-channel blockers. [ABSTRACT FROM AUTHOR]
ISSN:	00280836
DOI:	10.1038/nature06528