title: The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor.
abstract: Recent events have created an urgent need for new therapeutic strategies to treat anthrax. We have applied a mixture-based peptide library approach to rapidly determine the optimal peptide substrate for the anthrax lethal factor (LF), a metalloproteinase with an important role in the pathogenesis of the disease. Using this approach we have identified peptide analogs that inhibit the enzyme in vitro and that protect cultured macrophages from LF-mediated cytolysis. The crystal structures of LF bound to an optimized peptide substrate and to peptide-based inhibitors provide a rationale for the observed selectivity and may be exploited in the design of future generations of LF inhibitors.
authors.affiliation: Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.forename: Thiang Yian
authors.initials: TY
authors.lastname: Wong
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarzenbacher
authors.forename: Emily T
authors.initials: ET
authors.lastname: Jarrell
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: R John
authors.initials: RJ
authors.lastname: Collier
authors.forename: Robert C
authors.initials: RC
authors.lastname: Liddington
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000881:Anthrax / Q000188:drug therapy; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D046911:Macromolecular Substances; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D019151:Peptide Library; D013379:Substrate Specificity
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D046911:Macromolecular Substances; D009842:Oligopeptides; D019151:Peptide Library; C030325:anthrax toxin; D008666:Metalloendopeptidases