3WX2

Mouse Cereblon thalidomide binding domain, native

3WX2 の概要

• エントリーDOI: 10.2210/pdb3wx2/pdb
• 関連するPDBエントリー: 3WX1
• 分子名称: Protein cereblon, ZINC ION, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: zinc finger, e3 ubiquitin ligase, metal binding protein
• 由来する生物種: Mus musculus (mouse)
• 細胞内の位置: Cytoplasm (By similarity): Q8C7D2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 25185.61

構造登録者

Mori, T.,Ito, T.,Hirano, Y.,Yamaguchi, Y.,Handa, H.,Hakoshima, T. (登録日: 2014-07-10, 公開日: 2014-08-06, 最終更新日: 2023-11-08)

主引用文献

Chamberlain, P.P.,Lopez-Girona, A.,Miller, K.,Carmel, G.,Pagarigan, B.,Chie-Leon, B.,Rychak, E.,Corral, L.G.,Ren, Y.J.,Wang, M.,Riley, M.,Delker, S.L.,Ito, T.,Ando, H.,Mori, T.,Hirano, Y.,Handa, H.,Hakoshima, T.,Daniel, T.O.,Cathers, B.E.
Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs
Nat.Struct.Mol.Biol., 21:803-809, 2014

PubMed Abstract: The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. These drugs directly bind Cereblon (CRBN) and promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading to substrate ubiquitination and degradation. Here we present the crystal structure of human CRBN bound to DDB1 and the drug lenalidomide. A hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide, whereas the isoindolinone ring is exposed to solvent. We also solved the structures of the mouse TBD in the apo state and with thalidomide or pomalidomide. Site-directed mutagenesis in lentiviral-expression myeloma models showed that key drug-binding residues are critical for antiproliferative effects.

PubMed: 25108355
DOI: 10.1038/nsmb.2874

実験手法

X-RAY DIFFRACTION (2 Å)