Binding Hot Spots and Amantadine Orientation in the Influenza A Virus M2 Proton Channel
AUTOR(ES)
Chuang, Gwo-Yu
FONTE
The Biophysical Society
RESUMO
Structures of truncated versions of the influenza A virus M2 proton channel have been determined recently by x-ray crystallography in the open conformation of the channel, and by NMR in the closed state. The structures differ in the position of the bound inhibitors. The x-ray structure shows a single amantadine molecule in the middle of the channel, whereas in the NMR structure four drug molecules bind at the channel's outer surface. To study this controversy we applied computational solvent mapping, a technique developed for the identification of the most druggable binding hot spots of proteins. The method moves molecular probes—small organic molecules containing various functional groups—around the protein surface, finds favorable positions using empirical free energy functions, clusters the conformations, and ranks the clusters on the basis of the average free energy. The results of the mapping show that in both structures the primary hot spot is an internal cavity overlapping the amantadine binding site seen in the x-ray structure. However, both structures also have weaker hot spots at the exterior locations that bind rimantadine in the NMR structure, although these sites are partially due to the favorable interactions with the interfacial region of the lipid bilayer. As confirmed by docking calculations, the open channel binds amantadine at the more favorable internal site, in good agreement with the x-ray structure. In contrast, the NMR structure is based on a peptide/micelle construct that is able to accommodate the small molecular probes used for the mapping, but has a too narrow pore for the rimantadine to access the internal hot spot, and hence the drug can bind only at the exterior sites.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2776279Documentos Relacionados
- Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block.
- Selective proton permeability and pH regulation of the influenza virus M2 channel expressed in mouse erythroleukaemia cells.
- Definitive Assignment of Proton Selectivity and Attoampere Unitary Current to the M2 Ion Channel Protein of Influenza A Virus
- A functionally defined model for the M2 proton channel of influenza A virus suggests a mechanism for its ion selectivity
- Ion selectivity and activation of the M2 ion channel of influenza virus.