7BQU
Cereblon in complex with SALL4 and (S)-thalidomide
Summary for 7BQU
| Entry DOI | 10.2210/pdb7bqu/pdb |
| Descriptor | Protein cereblon, Sal-like protein 4, S-Thalidomide, ... (5 entities in total) |
| Functional Keywords | zinc finger, e3 ubiquitin ligase, complex, thalidomide, metal binding protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 16134.24 |
| Authors | Furihata, H.,Miyauchi, Y.,Asano, A.,Tanokura, M.,Miyakawa, T. (deposition date: 2020-03-25, release date: 2020-08-26, Last modification date: 2023-11-29) |
| Primary citation | Furihata, H.,Yamanaka, S.,Honda, T.,Miyauchi, Y.,Asano, A.,Shibata, N.,Tanokura, M.,Sawasaki, T.,Miyakawa, T. Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide. Nat Commun, 11:4578-4578, 2020 Cited by PubMed Abstract: Thalidomide and its derivatives exert not only therapeutic effects as immunomodulatory drugs (IMiDs) but also adverse effects such as teratogenicity, which are due in part to different C2H2 zinc-finger (ZF) transcription factors, IKZF1 (or IKZF3) and SALL4, respectively. Here, we report the structural bases for the SALL4-specific proteasomal degradation induced by 5-hydroxythalidomide, a primary thalidomide metabolite generated by the enzymatic activity of cytochrome P450 isozymes, through the interaction with cereblon (CRBN). The crystal structure of the metabolite-mediated human SALL4-CRBN complex and mutagenesis studies elucidate the complex formation enhanced by the interaction between CRBN and an additional hydroxy group of (S)-5-hydroxythalidomide and the variation in the second residue of β-hairpin structure that underlies the C2H2 ZF-type neo-morphic substrate (neosubstrate) selectivity of 5-hydroxythalidomide. These findings deepen our understanding of the pharmaceutical action of IMiDs and provide structural evidence that the glue-type E3 ligase modulators cause altered neosubstrate specificities through their metabolism. PubMed: 32929090DOI: 10.1038/s41467-020-18488-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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