Structural highlights
Disease
CRBN_HUMAN Autosomal recessive nonsyndromic intellectual deficit;Distal monosomy 3p. The disease is caused by mutations affecting the gene represented in this entry.
Function
CRBN_HUMAN Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1.[1] [2]
Publication Abstract from PubMed
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 beta-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.
Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide.,Furihata H, Yamanaka S, Honda T, Miyauchi Y, Asano A, Shibata N, Tanokura M, Sawasaki T, Miyakawa T Nat Commun. 2020 Sep 14;11(1):4578. doi: 10.1038/s41467-020-18488-4. PMID:32929090[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM. Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation. Neurogenetics. 2008 Jul;9(3):219-23. doi: 10.1007/s10048-008-0128-2. Epub 2008, Apr 15. PMID:18414909 doi:http://dx.doi.org/10.1007/s10048-008-0128-2
- ↑ Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H. Identification of a primary target of thalidomide teratogenicity. Science. 2010 Mar 12;327(5971):1345-50. doi: 10.1126/science.1177319. PMID:20223979 doi:http://dx.doi.org/10.1126/science.1177319
- ↑ 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. 2020 Sep 14;11(1):4578. PMID:32929090 doi:10.1038/s41467-020-18488-4
