Ligand-induced expansion of the S1′ site in the anthrax toxin lethal factor

Kimberly M. Maize, Elbek K. Kurbanov, Rodney L. Johnson, Elizabeth Ambrose Amin, Barry C. Finzel

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The Bacillus anthracis lethal factor (LF) is one component of a tripartite exotoxin partly responsible for persistent anthrax cytotoxicity after initial bacterial infection. Inhibitors of the zinc metalloproteinase have been investigated as potential therapeutic agents, but LF is a challenging target because inhibitors lack sufficient selectivity or possess poor pharmaceutical properties. These structural studies reveal an alternate conformation of the enzyme, induced upon binding of specific inhibitors, that opens a previously unobserved deep pocket termed S1′ which might afford new opportunities to design selective inhibitors that target this subsite.

Original languageEnglish (US)
Pages (from-to)3836-3841
Number of pages6
JournalFEBS Letters
Volume589
Issue number24
DOIs
StatePublished - Dec 21 2015

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (R01 AI083234 to E.A.A.). Support was also provided by an American Foundation for Pharmaceutical Education Pre-Doctoral Fellowship to K.M.M., a University of Minnesota Doctoral Dissertation Fellowship to E.K.K., the University of Minnesota College of Pharmacy to E.A.A., and the University of Minnesota Office of the Vice President for Research to E.A.A.

Funding Information:
The authors would like to thank Teresa De la Mora-Rey for collecting the data for structure 4XM6, as well as Jonathan Solberg and Jon Hawkinson of the Institute for Therapeutics Discovery and Development at the University of Minnesota for providing in vitro inhibition data. Use of beamline 17-ID (IMCA-CAT) of the Advanced Photon Source of Argonne National Laboratories was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. The Minnesota Supercomputing Institute for Advanced Computational Research is also gratefully acknowledged.

Publisher Copyright:
© 2015 Federation of European Biochemical Societies.

Keywords

  • Anthrax
  • Conformational change
  • Lethal factor
  • Ligand-induced
  • Structure-based drug design
  • Zinc hydrolase

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