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

Nature Structural & Molecular Biology volume 11, pages 60–66 (2004)Cite this article

Abstract

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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Figure 1: Inhibition of LF by GM6001.
Figure 2: Structures of LF in complex with peptides and inhibitors.

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Acknowledgements

Thanks to P. Bartlett (University of California Berkeley), D. Tronrud and B. Matthews (University of Oregon) and B. Rupp (Lawrence Livermore National Laboratory) for pointing out the canonical binding mode for Zn metalloproteases and to E. Garman (University of Oxford) and A. Gonzalez (SSRL) for discussions on the crystallography. We also thank H. Robinson and S. Vaday for collecting data at the National Synchrotron Light Source (NSLS). Portions of this research were carried out at the Stanford Synchrotron Radiation Laboratory (SSRL), a national user facility operated by Stanford University on behalf of the US Department of Energy (DOE), Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the DOE, Office of Biological and Environmental Research, and by the NIH, National Center for Research Resources, Biomedical Technology Program and the National Institute of General Medical Sciences. Data for this work were also collected at the NSLS, Brookhaven National Laboratory, which is supported by the DOE, Division of Materials Sciences and Division of Chemical Sciences, under contract no. DE-AC02-98CH10886. This work was supported by NIH (R.J.C., R.C.L. and L.C.C.), the US National Science Foundation (L.C.C.) and the US Department of the Army (DAMD17-03-1-0062 to L.C.C.). The US Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, Maryland 21702-5014 is the awarding and administering acquisition office. The contents of this manuscript do not necessarily reflect the position or policy of the US government, and no official endorsement should be inferred. B.E.T. is a Leukemia and Lymphoma Society special fellow.

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Author notes

  1. Benjamin E Turk and Thiang Yian Wong: These authors contributed equally to this work.

Authors and Affiliations

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

    Benjamin E Turk, Emily T Jarrell & Lewis C Cantley

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

    Thiang Yian Wong, Robert Schwarzenbacher & Robert C Liddington

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

    Stephen H Leppla

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

    R John Collier

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Correspondence to Robert C Liddington or Lewis C Cantley.

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One of the authors, R. John Collier, holds equity in the company Pharmathene, Inc.

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Turk, B., Wong, T., Schwarzenbacher, R. et al. The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor. Nat Struct Mol Biol 11, 60–66 (2004). https://doi.org/10.1038/nsmb708

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