1t84
From Proteopedia
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Solution structure of the Wiskott-Aldrich Syndrome Protein (WASP) autoinhibited core domain complexed with (S)-wiskostatin, a small molecule inhibitor
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Overview
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.
Disease
Known diseases associated with this structure: Neutropenia, severe congenital, X-linked OMIM:[300392], Thrombocytopenia, X-linked OMIM:[300392], Thrombocytopenia, X-linked, intermittent OMIM:[300392], Wiskott-Aldrich syndrome OMIM:[300392]
About this Structure
1T84 is a Single protein structure of sequence from Homo sapiens with WSK as ligand. Full crystallographic information is available from OCA.
Reference
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, Nat Struct Mol Biol. 2004 Aug;11(8):747-55. Epub 2004 Jul 4. PMID:15235593
Page seeded by OCA on Mon Nov 12 19:21:54 2007
