Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs
Copyright policy )Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs
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.
- Celgene United States
- Nara Institute of Science and Technology Japan
- Tokyo Medical University Japan
Protein Conformation, Ubiquitin-Protein Ligases, Molecular Sequence Data, Angiogenesis Inhibitors, Crystallography, X-Ray, Protein Structure, Tertiary, Thalidomide, DNA-Binding Proteins, Molecular Docking Simulation, Mice, Animals, Humans, Amino Acid Sequence, Lenalidomide, Sequence Alignment, Adaptor Proteins, Signal Transducing, Peptide Hydrolases, Protein Binding
Protein Conformation, Ubiquitin-Protein Ligases, Molecular Sequence Data, Angiogenesis Inhibitors, Crystallography, X-Ray, Protein Structure, Tertiary, Thalidomide, DNA-Binding Proteins, Molecular Docking Simulation, Mice, Animals, Humans, Amino Acid Sequence, Lenalidomide, Sequence Alignment, Adaptor Proteins, Signal Transducing, Peptide Hydrolases, Protein Binding
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).462 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 0.1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 1% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!