1t84
From Proteopedia
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|ACTIVITY= | |ACTIVITY= | ||
|GENE= WASP (residues 242-310 and 461-492) ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= WASP (residues 242-310 and 461-492) ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1ej5|1EJ5]], [[1cee|1CEE]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1t84 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1t84 OCA], [http://www.ebi.ac.uk/pdbsum/1t84 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1t84 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==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. | 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. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Neutropenia, severe congenital, X-linked OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300392 300392]], Thrombocytopenia, X-linked OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300392 300392]], Thrombocytopenia, X-linked, intermittent OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300392 300392]], Wiskott-Aldrich syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300392 300392]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Peterson, J R.]] | [[Category: Peterson, J R.]] | ||
[[Category: Rosen, M K.]] | [[Category: Rosen, M K.]] | ||
| - | [[Category: WSK]] | ||
[[Category: alpha helix]] | [[Category: alpha helix]] | ||
[[Category: beta-hairpin turn]] | [[Category: beta-hairpin turn]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:52:42 2008'' |
Revision as of 20:52, 30 March 2008
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| Ligands: | |||||||
| Gene: | WASP (residues 242-310 and 461-492) (Homo sapiens) | ||||||
| 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
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.
About this Structure
1T84 is a Single protein structure of sequence from Homo sapiens. 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
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