title: Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs.
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.
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Philip P
authors.initials: PP
authors.lastname: Chamberlain
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Lopez-Girona
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Miller
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Gilles
authors.initials: G
authors.lastname: Carmel
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Barbra
authors.initials: B
authors.lastname: Pagarigan
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Chie-Leon
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Rychak
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Corral
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Yan J
authors.initials: YJ
authors.lastname: Ren
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Wang
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Mariko
authors.initials: M
authors.lastname: Riley
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Delker
authors.affiliation: Tokyo Medical University, Tokyo, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Ito
authors.affiliation: Tokyo Medical University, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ando
authors.affiliation: Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mori
authors.affiliation: Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hirano
authors.affiliation: Tokyo Medical University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
authors.affiliation: Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hakoshima
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Daniel
authors.affiliation: Celgene Corporation, San Diego, California, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Cathers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D000077269:Lenalidomide; D051379:Mice; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; C502543:CRBN protein, human; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide
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