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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Peterson
authors.forename: Lincoln C
authors.initials: LC
authors.lastname: Bickford
authors.forename: David
authors.initials: D
authors.lastname: Morgan
authors.forename: Annette S
authors.initials: AS
authors.lastname: Kim
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.forename: Marc W
authors.initials: MW
authors.lastname: Kirschner
authors.forename: Michael K
authors.initials: MK
authors.lastname: Rosen
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000502:physiology*; D011412:Propanolamines / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013997:Time Factors; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D002227:Carbazoles; D009419:Nerve Tissue Proteins; D011412:Propanolamines; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; C489942:wiskostatin