Structural basis for the function and inhibition of an influenza virus proton channel
Top Cited Papers
- 31 January 2008
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 451 (7178), 596-599
- https://doi.org/10.1038/nature06528
Abstract
Until recently, the pH-gated proton channel of influenza A virus, M2, was effectively targeted by amantadine-based antivirals, but resistance to these drugs is now widespread. Two groups now present structural studies of M2 proton channel. Jason Schnell and James Chou determine the structure of a 38-residue segment of M2, in complex with rimantadine, by NMR spectroscopy. Amanda Stouffer et al. determined the crystal structure of a 25-residue fragment of M2, with and without amantadine, using X-ray diffraction. Strikingly, the resulting structures suggest two very different mechanisms by which the drug inhibits the channel. The proposed mechanisms are discussed by Christopher Miller in an accompanying News & Views article. A vital component of influenza A virus' replication machinery is the M2 proton channel. Until recently, M2 was effectively targeted by amantadane-based antivirals, but resistance to these drugs is now so widespread that they have become ineffective. In the second of two related manuscripts, the crystal structure of a 25-residue fragment of M2, both with and without amantadine, is described. It is concluded that a single amantadine molecule binds in the centre of the M2 tetramer to physically occlude the pore. 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 gating2. The drug-binding site is lined by residues that are mutated in amantadine-resistant viruses3,4. 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.Keywords
This publication has 124 references indexed in Scilit:
- Computational study of drug binding to the membrane-bound tetrameric M2 peptide bundle from influenza A virusBiochimica et Biophysica Acta (BBA) - Biomembranes, 2011
- Structural and dynamic mechanisms for the function and inhibition of the M2 proton channel from influenza A virusCurrent Opinion in Structural Biology, 2011
- Where does amantadine bind to the influenza virus M2 proton channel?Trends in Biochemical Sciences, 2010
- Conformational plasticity of the influenza A M2 transmembrane helix in lipid bilayers under varying pH, drug binding, and membrane thicknessBiochimica et Biophysica Acta (BBA) - Biomembranes, 2010
- Influenza Virus M2 Protein Mediates ESCRT-Independent Membrane ScissionCell, 2010
- Influence of solubilizing environments on membrane protein structuresTrends in Biochemical Sciences, 2010
- Binding Hot Spots and Amantadine Orientation in the Influenza A Virus M2 Proton ChannelBiophysical Journal, 2009
- Free‐energy profiles for ions in the influenza M2‐TMD channelProteins-Structure Function and Bioinformatics, 2009
- The Interplay of Functional Tuning, Drug Resistance, and Thermodynamic Stability in the Evolution of the M2 Proton Channel from the Influenza A VirusStructure, 2008
- Solid-state NMR characterization of conformational plasticity within the transmembrane domain of the influenza A M2 proton channelBiochimica et Biophysica Acta (BBA) - Biomembranes, 2007