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  • 1
    Publication Date: 2014-07-22
    Description: In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423819/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423819/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fischer, Eric S -- Bohm, Kerstin -- Lydeard, John R -- Yang, Haidi -- Stadler, Michael B -- Cavadini, Simone -- Nagel, Jane -- Serluca, Fabrizio -- Acker, Vincent -- Lingaraju, Gondichatnahalli M -- Tichkule, Ritesh B -- Schebesta, Michael -- Forrester, William C -- Schirle, Markus -- Hassiepen, Ulrich -- Ottl, Johannes -- Hild, Marc -- Beckwith, Rohan E J -- Harper, J Wade -- Jenkins, Jeremy L -- Thoma, Nicolas H -- AG011085/AG/NIA NIH HHS/ -- R01 AG011085/AG/NIA NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):49-53. doi: 10.1038/nature13527. Epub 2014 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland. ; Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA. ; Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. ; 1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland [2] University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland [3] Swiss Institute of Bioinformatics, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. ; Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043012" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; DNA-Binding Proteins/agonists/antagonists & inhibitors/chemistry/metabolism ; Homeodomain Proteins/metabolism ; Humans ; Models, Molecular ; Multiprotein Complexes/agonists/antagonists & inhibitors/chemistry/metabolism ; Peptide Hydrolases/*chemistry/metabolism ; Protein Binding ; Structure-Activity Relationship ; Substrate Specificity ; Thalidomide/analogs & derivatives/*chemistry/metabolism ; Transcription Factors/metabolism ; Ubiquitin-Protein Ligases/antagonists & inhibitors/*chemistry/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2009-09-18
    Description: The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Shih-Min A -- Mishina, Yuji M -- Liu, Shanming -- Cheung, Atwood -- Stegmeier, Frank -- Michaud, Gregory A -- Charlat, Olga -- Wiellette, Elizabeth -- Zhang, Yue -- Wiessner, Stephanie -- Hild, Marc -- Shi, Xiaoying -- Wilson, Christopher J -- Mickanin, Craig -- Myer, Vic -- Fazal, Aleem -- Tomlinson, Ronald -- Serluca, Fabrizio -- Shao, Wenlin -- Cheng, Hong -- Shultz, Michael -- Rau, Christina -- Schirle, Markus -- Schlegl, Judith -- Ghidelli, Sonja -- Fawell, Stephen -- Lu, Chris -- Curtis, Daniel -- Kirschner, Marc W -- Lengauer, Christoph -- Finan, Peter M -- Tallarico, John A -- Bouwmeester, Tewis -- Porter, Jeffery A -- Bauer, Andreas -- Cong, Feng -- England -- Nature. 2009 Oct 1;461(7264):614-20. doi: 10.1038/nature08356. Epub 2009 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19759537" target="_blank"〉PubMed〈/a〉
    Keywords: Axin Protein ; Cell Division/drug effects ; Cell Line ; Cell Line, Tumor ; Colorectal Neoplasms/drug therapy/metabolism ; Heterocyclic Compounds, 3-Ring/pharmacology ; Humans ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Proteomics ; Repressor Proteins/chemistry/*metabolism ; Signal Transduction/*drug effects ; Tankyrases/*antagonists & inhibitors/metabolism ; Transcription, Genetic/drug effects ; Ubiquitin/metabolism ; Ubiquitination ; Wnt Proteins/*antagonists & inhibitors/metabolism ; beta Catenin/antagonists & inhibitors/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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