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Nat Struct Mol Biol. August 1, 2004; 11 (8): 747-55.

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

Peterson JR , Bickford LC , Morgan D , Kim AS , Ouerfelli O , Kirschner MW , Rosen MK .

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.

PubMed ID: 15235593
Article link: Nat Struct Mol Biol.
Grant support: GM07739 NIGMS NIH HHS , GM197000 NIGMS NIH HHS , GM56322 NIGMS NIH HHS

Genes referenced: was wasl

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