Dominant-negative mutants of a toxin subunit: an approach to therapy of anthrax.
The protective antigen moiety of anthrax toxin translocates the toxin's enzymic moieties to the cytosol of mammalian cells by a mechanism that depends on its ability to heptamerize and insert into membranes. We identified dominant-negative mutants of protective antigen that co-assemble with the wild-type protein and block its ability to translocate the enzymic moieties across membranes. These mutants strongly inhibited toxin action in cell culture and in an animal intoxication model, suggesting that they could be useful in therapy of anthrax.
Sellman
B R
BR
Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA.
Mourez
M
M
Collier
R J
RJ
D000818:Animals; D000881:Anthrax / Q000188:drug therapy*; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004705:Endocytosis; D005799:Genes, Dominant; D008297:Male; D009154:Mutation; D021381:Protein Transport; D051381:Rats; D011916:Rats, Inbred F344; D018000:Receptors, Peptide / Q000378:metabolism
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D018000:Receptors, Peptide; C030325:anthrax toxin; C070309:anthrax toxin receptors