Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs
| العنوان: | Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs |
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| المؤلفون: | Philip P Chamberlain, Maria Wang, Yoshinori Hirano, Brian E. Cathers, Gilles Carmel, Toshio Hakoshima, Hiroshi Handa, Barbra Pagarigan, Emily Rychak, Yan J Ren, Barbara Chie-Leon, Silvia L. Delker, Laura G. Corral, Tomoyuki Mori, Takumi Ito, Thomas O. Daniel, Antonia Lopez-Girona, Karen Miller, Hideki Ando, Mariko Riley |
| المصدر: | Nature Structural & Molecular Biology. 21:803-809 |
| بيانات النشر: | Springer Science and Business Media LLC, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Protein Conformation, Ubiquitin-Protein Ligases, Molecular Sequence Data, Angiogenesis Inhibitors, Crystallography, X-Ray, Mice, DDB1, Ubiquitin, Structural Biology, medicine, Animals, Humans, Amino Acid Sequence, Lenalidomide, Molecular Biology, Adaptor Proteins, Signal Transducing, biology, Cereblon, Protein Cereblon, IKZF3, Protein Structure, Tertiary, Thalidomide, Ubiquitin ligase, DNA-Binding Proteins, Molecular Docking Simulation, Biochemistry, biology.protein, Cancer research, Sequence Alignment, Peptide Hydrolases, Protein Binding, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1545-9985 1545-9993 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7b131abf0f427feaba8ec6b36dad4572 https://doi.org/10.1038/nsmb.2874 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....7b131abf0f427feaba8ec6b36dad4572 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15459985 15459993 |
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