1T84

Solution structure of the Wiskott-Aldrich Syndrome Protein (WASP) autoinhibited core domain complexed with (S)-wiskostatin, a small molecule inhibitor

1T84 の概要

• エントリーDOI: 10.2210/pdb1t84/pdb
• 関連するPDBエントリー: 1CEE 1EJ5
• 分子名称: Wiskott-Aldrich syndrome protein, (2S)-1-(3,6-DIBROMO-9H-CARBAZOL-9-YL)-3-(DIMETHYLAMINO)PROPAN-2-OL (2 entities in total)
• 機能のキーワード: alpha helix, beta-hairpin turn, signaling protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton: P42768
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12029.74

構造登録者

Peterson, J.R.,Bickford, L.C.,Morgan, D.,Kim, A.S.,Ouerfelli, O.,Kirschner, M.W.,Rosen, M.K. (登録日: 2004-05-11, 公開日: 2004-07-13, 最終更新日: 2024-05-22)

主引用文献

Peterson, J.R.,Bickford, L.C.,Morgan, D.,Kim, A.S.,Ouerfelli, O.,Kirschner, M.W.,Rosen, M.K.
Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation.
Nat.Struct.Mol.Biol., 11:747-755, 2004

PubMed 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.

PubMed: 15235593
DOI: 10.1038/nsmb796

実験手法

SOLUTION NMR