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Article
Nature Structural & Molecular Biology  11, 60 - 66 (2003)
Published online: 29 December 2003; | doi:10.1038/nsmb708

The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor

Benjamin E Turk1, 5, Thiang Yian Wong2, 5, Robert Schwarzenbacher2, Emily T Jarrell1, Stephen H Leppla3, R John Collier4, Robert C Liddington2 & Lewis C Cantley1

1  Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, and Department of Cell Biology, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.

2  The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.

3  National Institute of Allergy and Infectious Diseases, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.

4  Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.

5  These authors contributed equally to this work.

Correspondence should be addressed to Robert C Liddington rlidding@burnham.org or Lewis C Cantley lewis_cantley@hms.harvard.edu
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.

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Nature Structural & Molecular Biology
ISSN: 1545-9993
EISSN: 1545-9985
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