| Title |
Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs
|
|---|---|
| Published in |
Nature Structural & Molecular Biology, August 2014
|
| DOI | 10.1038/nsmb.2874 |
| Pubmed ID | |
| Authors |
Philip P Chamberlain, Antonia Lopez-Girona, Karen Miller, Gilles Carmel, Barbra Pagarigan, Barbara Chie-Leon, Emily Rychak, Laura G Corral, Yan J Ren, Maria Wang, Mariko Riley, Silvia L Delker, Takumi Ito, Hideki Ando, Tomoyuki Mori, Yoshinori Hirano, Hiroshi Handa, Toshio Hakoshima, Thomas O Daniel, Brian E Cathers |
| 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. |
X Demographics
The data shown below were collected from the profiles of 14 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 3 | 21% |
| Japan | 2 | 14% |
| Germany | 1 | 7% |
| Slovenia | 1 | 7% |
| Unknown | 7 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 10 | 71% |
| Scientists | 4 | 29% |
Mendeley readers
The data shown below were compiled from readership statistics for 429 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 4 | <1% |
| Germany | 2 | <1% |
| Japan | 2 | <1% |
| Brazil | 1 | <1% |
| India | 1 | <1% |
| Belgium | 1 | <1% |
| France | 1 | <1% |
| United Kingdom | 1 | <1% |
| Denmark | 1 | <1% |
| Other | 0 | 0% |
| Unknown | 415 | 97% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 86 | 20% |
| Student > Ph. D. Student | 76 | 18% |
| Student > Master | 40 | 9% |
| Student > Bachelor | 37 | 9% |
| Other | 26 | 6% |
| Other | 62 | 14% |
| Unknown | 102 | 24% |
| Readers by discipline | Count | As % |
|---|---|---|
| Chemistry | 97 | 23% |
| Biochemistry, Genetics and Molecular Biology | 83 | 19% |
| Agricultural and Biological Sciences | 59 | 14% |
| Medicine and Dentistry | 26 | 6% |
| Pharmacology, Toxicology and Pharmaceutical Science | 23 | 5% |
| Other | 25 | 6% |
| Unknown | 116 | 27% |
Attention Score in Context
This research output has an Altmetric Attention Score of 60. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 31 October 2023.
All research outputs
#707,886
of 25,374,917 outputs
Outputs from Nature Structural & Molecular Biology
#242
of 4,186 outputs
Outputs of similar age
#6,692
of 242,450 outputs
Outputs of similar age from Nature Structural & Molecular Biology
#1
of 40 outputs
Altmetric has tracked 25,374,917 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 97th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
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