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

Jeffrey R. Peterson, Lincoln C. Bickford, David Morgan, Annette S. Kim, Ouathek Ouerfelli, Marc W. Kirschner, Michael K. Rosen

Research output: Contribution to journalArticlepeer-review

161 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)747-755
Number of pages9
JournalNature Structural and Molecular Biology
Issue number8
StatePublished - Aug 2004

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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