Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation Journal Article
| Authors: | Peterson, J. R.; Bickford, L. C.; Morgan, D.; Kim, A. S.; Ouerfelli, O.; Kirschner, M. W.; Rosen, M. K. |
| Article Title: | Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation |
| 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. |
| Keywords: | signal transduction; unclassified drug; protein conformation; protein domain; animals; complex formation; protein protein interaction; nerve tissue proteins; protein stability; dose-response relationship, drug; drug design; structure-activity relationship; time factors; magnetic resonance spectroscopy; cytoplasm; binding site; models, molecular; protein structure, tertiary; binding sites; catalysis; protein folding; protein structure; models, chemical; protein isolation; carbazoles; propanolamines; wiskott-aldrich syndrome protein, neuronal; xenopus laevis; allosterism; guanosine triphosphatase; wiskott aldrich syndrome protein; allosteric site; priority journal; article; wiskostatin |
| Journal Title: | Nature Structural and Molecular Biology |
| Volume: | 11 |
| Issue: | 8 |
| ISSN: | 1545-9993 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2004-08-01 |
| Start Page: | 747 |
| End Page: | 755 |
| Language: | English |
| DOI: | 10.1038/nsmb796 |
| PROVIDER: | scopus |
| PUBMED: | 15235593 |
| DOI/URL: | |
| Notes: | Nat. Struct. Mol. Biol. -- Cited By (since 1996):87 -- Export Date: 16 June 2014 -- CODEN: NSMBC -- Source: Scopus |
