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Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation

Nature Structural & Molecular Biology volume 11, pages 747755 (2004) | Download Citation

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Abstract

Current drug discovery efforts focus primarily on proteins with defined enzymatic or small molecule binding sites. Autoregulatory domains represent attractive alternative targets for small molecule inhibitors because they also occur in noncatalytic proteins and because allosteric inhibitors may avoid specificity problems inherent in active site–directed inhibitors. We report here the identification of wiskostatin, a chemical inhibitor of the neural Wiskott-Aldrich syndrome protein (N-WASP). Wiskostatin interacts with a cleft in the regulatory GTPase-binding domain (GBD) of WASP in the solution structure of the complex. Wiskostatin induces folding of the isolated, unstructured GBD into its autoinhibited conformation, suggesting that wiskostatin functions by stabilizing N-WASP in its autoinhibited state. The use of small molecules to bias conformational equilibria represents a potentially general strategy for chemical inhibition of autoinhibited proteins, even in cases where such sites have not been naturally evolved in a target.

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Acknowledgements

We thank N. Ayad, S. Eden and G. Hoffmann for critical reading of the manuscript and A. Majumdar for assistance with NMR spectra. This work was supported by grants from the US National Institutes of Health (J.R.P., GM197000; L.C.B., GM07739; M.K.R., GM56322), the Welch Foundation (I–1544, M.K.R.) and the Cancer Research Institute (D.M.).

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Author notes

    • Jeffrey R Peterson

    Present address: Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, USA.

    • Jeffrey R Peterson
    •  & Lincoln C Bickford

    These authors contributed equally to this work.

Affiliations

  1. Department of Cell Biology and Department of Systems Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.

    • Jeffrey R Peterson
    •  & Marc W Kirschner
  2. Structural Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.

    • Lincoln C Bickford
    •  & Ouathek Ouerfelli
  3. Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.

    • David Morgan
    •  & Michael K Rosen
  4. Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, 6 Founders Pavilion, Philadelphia, Pennsylvania 19104, USA.

    • Annette S Kim

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Marc W Kirschner or Michael K Rosen.

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DOI

https://doi.org/10.1038/nsmb796

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