DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras
| العنوان: | DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras |
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| المؤلفون: | Kristen A. Baltgalvis, Vincent M. Crowley, Michael A. Schafroth, Brian E. Nordin, Benjamin F. Cravatt, Christie L Eissler, Joe L Rodriguez, Shota Kikuchi, Xiaoyu Zhang, Thomas G Wucherpfennig, Todd Kinsella, Kent T Symons, Melissa M. Dix, David S. Weinstein, Dean Stamos, Gabriel M. Simon, Yu Yamashita, Ludwig Bauer, Lena M Luukkonen |
| المصدر: | J Am Chem Soc |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Proteasome Endopeptidase Complex, Proteolysis, Protein degradation, 010402 general chemistry, 01 natural sciences, Biochemistry, Article, Catalysis, Chimera (genetics), Colloid and Surface Chemistry, Cell Line, Tumor, medicine, Humans, Receptor, medicine.diagnostic_test, biology, Ubiquitin, Chemistry, Prostatic Neoplasms, Ubiquitin-Protein Ligase Complexes, General Chemistry, 0104 chemical sciences, Ubiquitin ligase, Cell biology, Androgen receptor, Receptors, Androgen, Cell culture, Cancer cell, biology.protein |
| الوصف: | Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases. Mechanistic studies revealed that the electrophilic PROTACs act through modifying specific cysteines in DCAF11, a poorly characterized E3 ligase substrate adaptor. We further show that DCAF11-directed electrophilic PROTACs can degrade multiple endogenous proteins, including FBKP12 and the androgen receptor, in human prostate cancer cells. Our findings designate DCAF11 as an E3 ligase capable of supporting ligand-induced protein degradation via electrophilic PROTACs. |
| تدمد: | 1520-5126 0002-7863 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a9801b3a3bafd3e374259ca9ad1a1524Test https://doi.org/10.1021/jacs.1c00990Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a9801b3a3bafd3e374259ca9ad1a1524 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15205126 00027863 |
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