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

Rickey Paige Hicks, Apurba K. Bhattacharjee, Brandon W. Koser, Daniel D. Traficante

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5347-5355
Number of pages9
JournalJournal of Medicinal Chemistry
Volume47
Issue number22
DOIs
StatePublished - Oct 21 2004

Fingerprint

Peptides
Bacillus anthracis
Gram-Positive Bacteria
Bacteriophages
anthrax toxin
Enzymes
edema factor
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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. / Hicks, Rickey Paige; Bhattacharjee, Apurba K.; Koser, Brandon W.; Traficante, Daniel D.

In: Journal of Medicinal Chemistry, Vol. 47, No. 22, 21.10.2004, p. 5347-5355.

Research output: Contribution to journalArticle

Hicks, Rickey Paige ; Bhattacharjee, Apurba K. ; Koser, Brandon W. ; Traficante, Daniel D. / 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. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 22. pp. 5347-5355.
@article{6fa402674eef44ab83768af126241146,
title = "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",
abstract = "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.",
author = "Hicks, {Rickey Paige} and Bhattacharjee, {Apurba K.} and Koser, {Brandon W.} and Traficante, {Daniel D.}",
year = "2004",
month = "10",
day = "21",
doi = "10.1021/jm040139a",
language = "English (US)",
volume = "47",
pages = "5347--5355",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "22",

}

TY - JOUR

T1 - The anthrax protective antigen (PA63) bound conformation of a peptide inhibitor of the binding of lethal factor to PA63

T2 - As determined by trNOESY NMR and molecular modeling

AU - Hicks, Rickey Paige

AU - Bhattacharjee, Apurba K.

AU - Koser, Brandon W.

AU - Traficante, Daniel D.

PY - 2004/10/21

Y1 - 2004/10/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=6044224897&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=6044224897&partnerID=8YFLogxK

U2 - 10.1021/jm040139a

DO - 10.1021/jm040139a

M3 - Article

VL - 47

SP - 5347

EP - 5355

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 22

ER -