The anthrax protective antigen (PA63) bound conformation of a peptide inhibitor of the binding of lethal factor to PA63: as determined by trNOESY NMR and molecular modeling

J Med Chem. 2004 Oct 21;47(22):5347-55. doi: 10.1021/jm040139a.


Anthrax protective antigen (PA) is one of the three proteins produced by the gram positive bacteria Bacillus anthracis collectively known as the "anthrax toxin" (Ascenzi, P.; Visca, P.; Ippolito, G.; Spallarossa, A.; Bolognesi, M.; et al. Anthrax toxin: a tripartite lethal combination. FEBS Lett. 2002, 531, 384-388). The role played by PA in anthrax intoxication is to transport the two enzymes lethal factor (LF) and edema factor (EF) into the cell. Collier and co-workers (Mourez, M.; Kane, R. S.; Mogridge, J.; Metallo, S.; Deschatelets, P.; et al. Designing a polyvalent inhibitor of anthrax toxin. Nat. Biotechnol. 2001, 958). reported the isolation of two peptides via phage display that bind to the PA63 heptamer and inhibit its interaction with LF and EF, and thereby prevent the transport of LF and EF into the cell. One of these peptides, His-Thr-Ser-Thr-Try-Trp-Trp-Leu-Asp-Gly-Ala-Pro (P1), was selected for structural investigation on the basis of its ability to prevent the binding of LF to the PA63 heptamer bundle. Two-dimensional trNOESY experiments coupled with NOE restrained simulated annealing calculations were used to determine the PA63-bound conformation of P1. On binding to PA63, P1 adopts a helical conformation involving residues 3-9 while the C- and N-terminal residues exhibit dynamic fraying.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Antigens, Bacterial / chemistry*
  • Antigens, Bacterial / metabolism
  • Bacillus anthracis / chemistry*
  • Bacillus anthracis / physiology
  • Bacterial Toxins / chemistry*
  • Bacterial Toxins / metabolism
  • Magnetic Resonance Spectroscopy / methods
  • Models, Molecular
  • Oligopeptides / chemistry*
  • Oligopeptides / metabolism
  • Protein Binding
  • Protein Structure, Secondary
  • Solutions
  • Water


  • Anti-Bacterial Agents
  • Antigens, Bacterial
  • Bacterial Toxins
  • Oligopeptides
  • Solutions
  • anthrax toxin
  • histidyl-threonyl-seryl-threonyl-tyrosyl-tryptophyl-tryptophyl-leucyl-aspartyl-glycyl-alanyl-proline
  • Water