Drug sensitivity, drug-resistant mutations, and structures of three conductance domains of viral porins.
Recent controversies associated with the structure of the M2 protein from influenza A virus and the binding site of drug molecules amantadine and rimantadine motivated the comparison here of the drug binding to three viral porins including the M2 proteins from influenza A and B as well as the viral protein 'u' from HIV-1. While the M2 protein from influenza B does not normally bind amantadine, chimeras with the M2 protein from influenza A show blockage by amantadine. Similarly, Vpu does not normally bind rimantadine, but the single site mutation A18H converts a non-specific channel to a selective proton channel that is sensitive to rimantadine. The comparison of structures and amino acid sequences shows that the membrane protein sample environment can have a significant influence on the structural result. While a bilayer surface bound amphipathic helix has been characterized for AM2, such a helix may be possible for BM2 although it has evaded structural characterization in detergent micelles. A similar amphipathic helix seems less likely for Vpu. Even though the A18H Vpu mutant forms rimantadine sensitive proton channels, the binding of drug and its influence on the protein structure appears to be very different from that for the M2 proteins. Indeed, drug binding and drug resistance in these viral porins appears to result from a complex set of factors.
Sharma
Mukesh
M
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32310, USA.
Li
Conggang
C
Busath
David D
DD
Zhou
Huan-Xiang
HX
Cross
Timothy A
TA
D000595:Amino Acid Sequence; D001665:Binding Sites; D024882:Drug Resistance, Viral / Q000235:genetics; D004553:Electric Conductivity; D005814:Genes, Viral; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry / Q000235:genetics; D009980:Influenza A virus / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D009981:Influenza B virus / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D018272:Porins / Q000737:chemistry* / Q000235:genetics*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000235:genetics; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000235:genetics; D000086082:Viroporin Proteins
D054298:Human Immunodeficiency Virus Proteins; D018272:Porins; D011993:Recombinant Fusion Proteins; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C514859:vpu protein, Human immunodeficiency virus 1