Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs

被引：406

作者：

Chamberlain, Philip P. ^{[1
]}

Lopez-Girona, Antonia ^{[1
]}

Miller, Karen ^{[1
]}

Carmel, Gilles ^{[1
]}

Pagarigan, Barbra ^{[1
]}

Chie-Leon, Barbara ^{[1
]}

Rychak, Emily ^{[1
]}

Corral, Laura G. ^{[1
]}

Ren, Yan J. ^{[1
]}

Wang, Maria ^{[1
]}

Riley, Mariko ^{[1
]}

Delker, Silvia L. ^{[1
]}

Ito, Takumi ^{[2
]}

Ando, Hideki ^{[2
]}

Mori, Tomoyuki ^{[3
]}

Hirano, Yoshinori ^{[3
]}

Handa, Hiroshi ^{[2
]}

Hakoshima, Toshio ^{[3
]}

Daniel, Thomas O. ^{[1
]}

Cathers, Brian E. ^{[1
]}

机构：

[1] Celgene Corp, San Diego, CA 92121 USA

[2] Tokyo Med Univ, Tokyo 1608402, Japan

[3] Nara Inst Sci & Technol, Nara 6300101, Japan

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2014年 / 21卷 / 09期

基金：

日本学术振兴会; 加拿大自然科学与工程研究理事会; 美国国家卫生研究院; 加拿大健康研究院;

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; LENALIDOMIDE; CEREBLON; MECHANISM; PROTEINS; RECEPTOR; BINDING; DESTRUCTION; DEGRADATION; REPRESSORS;

D O I：

10.1038/nsmb.2874

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

收藏

页码：803 / 809

页数：7

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