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1t84
From Proteopedia
| 1t84, 20 NMR models () | |||||||||
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| Ligands: | |||||||||
| Gene: | WASP (residues 242-310 and 461-492) (Homo sapiens) | ||||||||
| Domains: | CRIB | ||||||||
| Related: | 1ej5, 1cee | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Solution structure of the Wiskott-Aldrich Syndrome Protein (WASP) autoinhibited core domain complexed with (S)-wiskostatin, a small molecule inhibitor
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.
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
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
1T84 is a 1 chain structure of sequence from Homo sapiens. Full experimental information is available from OCA.
Reference
- Peterson JR, Bickford LC, Morgan D, Kim AS, Ouerfelli O, Kirschner MW, Rosen MK. Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation. Nat Struct Mol Biol. 2004 Aug;11(8):747-55. Epub 2004 Jul 4. PMID:15235593 doi:10.1038/nsmb796
Page seeded by OCA on Mon Feb 16 17:01:58 2009
