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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Amino Acid Sequence
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Crystallography, X-Ray
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism*
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Humans
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Lenalidomide
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Mice
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Molecular Docking Simulation
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Molecular Sequence Data
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Peptide Hydrolases / chemistry
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Peptide Hydrolases / metabolism*
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Protein Binding
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Protein Conformation
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Protein Structure, Tertiary
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Sequence Alignment
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Thalidomide / analogs & derivatives*
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Thalidomide / chemistry
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Thalidomide / pharmacology
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Ubiquitin-Protein Ligases
Substances
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Adaptor Proteins, Signal Transducing
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Angiogenesis Inhibitors
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CRBN protein, human
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DDB1 protein, human
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DNA-Binding Proteins
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Thalidomide
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Ubiquitin-Protein Ligases
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Peptide Hydrolases
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Lenalidomide
Associated data
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PDB/3WX2
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PDB/4TZ4
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PDB/4TZC
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PDB/4TZU