Influenza virus M2 protein: a molecular modelling study of the ion channel.
The influenza A M2 protein forms cation-selective ion channels which are blocked by the anti-influenza drug amantadine. A molecular model of the M2 channel is presented in which a bundle of four parallel M2 transbilayer helices surrounds a central ion-permeable pore. Analysis of helix amphipathicity was used to aid determination of the orientation of the helices about their long axes. The helices are tilted such that the N-terminal mouth of the pore is wider than the C-terminal mouth. The channel is lined by residues V27, S31 and I42. Residues D24 and D44 are located at opposite mouths of the pore, which is narrowest in the vicinity of I42. Energy profiles for interaction of the channel with Na+, amantadine-H+ and cyclopentylamine-H+ are evaluated. The interaction profile for Na+ exhibits three minima, one at each mouth of the pore, and one in the region of residue S31. The amantadine-H+ profile exhibits a minimum close to S31 and a barrier near residue I42. This provides a molecular model for amantadine-H+ block of M2 channels. The profile for cyclopentylamine-H+ does not exhibit such a barrier. It is predicted that cyclopentylamine-H+ will not act as an M2 channel blocker.
Sansom
M S
MS
Laboratory of Molecular Biophysics, University of Oxford, UK.
Kerr
I D
ID
D000547:Amantadine / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D003517:Cyclopentanes / Q000737:chemistry / Q000378:metabolism; D009980:Influenza A virus / Q000737:chemistry*; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011522:Protons; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism; D012964:Sodium / Q000737:chemistry / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D000086082:Viroporin Proteins
D000547:Amantadine; D003517:Cyclopentanes; D007473:Ion Channels; D011522:Protons; D011978:Receptors, Nicotinic; D012964:Sodium; D014763:Viral Matrix Proteins; C031540:M-protein, influenza virus; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C016329:cyclopentylamine