Lethal factor interacts with several MAPKK molecules as mentioned on the biological function page. Below I have discussed the interactions LF has with small molecules such as inhibitors. 

Structure of LF in complex with peptides and inhibitors

Electron cloud density map of anthrax lethal factor with bound substrates shown with ball and stick models. The red patches indicate negative charge while the blue indicates positive charge. Image courtesy of

Protein Screening, LF Inhibition Edit

Turk et al. (2003) ran an extensive peptide screen on potential lethal factor substrates.
GM6001 (galardin or ilomastat) metalloproteinase inhibitor

Bond line diagram of GM6001, also known as galardin or ilomastat. Image from

They also tested a wide range of metalloproteinase inhibitors on their ability to inhibit lethal factor. Binding assays were run to detect the efficiency of the substrates' inhibition using enzyme kinetics. The researchers found that a peptide called LF20, and two metalloproteinase inhibitor molecules GM6001 and SHAc-YPM were highly successful LF inhibitors. These molecules were shown (via enzyme kinetics and crystallography) to bind in the major groove of the LF protein and prevent binding of MAPKK's. The peptide pools were designed by examining the cleavage sites of MAPKK's and the specificity of the sites themselves. They found that LF requires a hydrophobic amino acid at position P1 (one of several clevage positions) among other selective parameters. Thus, peptides were designed so that these parameters were altered slightly as to conserve the binding of the substrate but tweak the cleavage site so that the engineered peptides would remain docked. 


Curcumin Derivatives

Native curcumin (compound 1) along with four other chemically modified cur cumin derivatives. Photo courtesy of

Curcumin, the active ingredient of the eastern spice turmeric (Curcuma longa) popular in Asian countries is known to have many medicinal purposes. Becuase of its many functional groups, curcumin, in small amounts can act as an anti-inflammatory, protein kinase, and prion among other things. Antonelli et al. (2013) ran assays to test the effect of Curcumin on lethal factor inhibition. They tested five chemically modified curcumin derivatives and found that all compounds except compound two were able to inhibit lethal factors peptidolytic activity. Unlike the study done by Turk et al. (2003), the curcumin molecules were found to not only competitively inhibit lethal factor, but were also able to bind to allosteric sites (compounds one and three) and funciton as noncompetitive inhibitors as well. 

Project PagesEdit

  1. Patrick: Anthrax Toxin: Introduction 
  2. Patrick: Anthrax Toxin: Biological Function
  3. Patrick: Anthrax Toxin: Biosynthesis
  4. Patrick: Anthrax Toxin: Gene Sequence
  5. Patrick: Anthrax Toxin: Amino Acid Sequence and Composition
  6. Patrick: Anthrax Toxin: Secondary and Tertiary Structure
  7. Patrick: Anthrax Toxin: Domains and Structural Motifs
  8. Patrick: Anthrax Toxin: Interactions with macromolecules and small molecules
  9. Patrick: Anthrax Toxin: Molecular biodiversity and evolution
  10. Patrick: Anthrax Toxin: PyMOL Images
  11. Patrick: Anthrax Toxin: Literature Review
  12. Patrick: Anthrax Toxin: Useful online resources

References Edit

Antonelli, A., Zhang, Y., Golub, L., Johnson, F., Simon, S. 2013. Inhibition of anthrax lethal factor by curcumin and chemically modified curcumin derivativesJournal of Enzyme Inhibition and Medicinal Chemistry. Epub ahead of print. 

Dalkas, G., Papakyriakou, A., Vlamis-Gardikas, A., Spyroulias, G. 2009. Insights into the anthrax lethal factor–substrate interaction and selectivity using docking and molecular dynamics simulationsProtein Science. 18 (8):1774-1785 

Nestorovoch EM, Bezrukov SM. 2014. Designing Inhibitors of Anthrax ToxinInforma Health Care. 9(3):299-318

Turk, B. et al. 2003. The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor.Nature Structural and Molecular Biology. 11(1):60-66.

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