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Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16

Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, however, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy that leverages broadly reactiv...

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Detalles Bibliográficos
Autores principales: Zhang, Xiaoyu, Crowley, Vincent M., Wucherpfennig, Thomas G., Dix, Melissa M., Cravatt, Benjamin F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592777/
https://www.ncbi.nlm.nih.gov/pubmed/31209349
http://dx.doi.org/10.1038/s41589-019-0279-5
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author Zhang, Xiaoyu
Crowley, Vincent M.
Wucherpfennig, Thomas G.
Dix, Melissa M.
Cravatt, Benjamin F.
author_facet Zhang, Xiaoyu
Crowley, Vincent M.
Wucherpfennig, Thomas G.
Dix, Melissa M.
Cravatt, Benjamin F.
author_sort Zhang, Xiaoyu
collection PubMed
description Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, however, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy that leverages broadly reactive, cysteine-directed electrophilic fragments coupled to selective ligands for intracellular proteins (e.g., SLF for FKBP12, JQ1 for BRD4) to screen for heterobifunctional degrader compounds (or PROTACs) that operate by covalent adduction of E3 ligases. This approach identified DCAF16 – a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases – as a target of electrophilic PROTACs that promote the nuclear-restricted degradation of proteins. We find that only a modest fraction (~10-40%) of DCAF16 needs to be modified to support protein degradation, pointing to the potential for electrophilic PROTACs to induce neo-substrate degradation without substantially perturbing the function of the participating E3 ligase.
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spelling pubmed-65927772019-12-17 Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16 Zhang, Xiaoyu Crowley, Vincent M. Wucherpfennig, Thomas G. Dix, Melissa M. Cravatt, Benjamin F. Nat Chem Biol Article Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, however, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy that leverages broadly reactive, cysteine-directed electrophilic fragments coupled to selective ligands for intracellular proteins (e.g., SLF for FKBP12, JQ1 for BRD4) to screen for heterobifunctional degrader compounds (or PROTACs) that operate by covalent adduction of E3 ligases. This approach identified DCAF16 – a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases – as a target of electrophilic PROTACs that promote the nuclear-restricted degradation of proteins. We find that only a modest fraction (~10-40%) of DCAF16 needs to be modified to support protein degradation, pointing to the potential for electrophilic PROTACs to induce neo-substrate degradation without substantially perturbing the function of the participating E3 ligase. 2019-06-17 2019-07 /pmc/articles/PMC6592777/ /pubmed/31209349 http://dx.doi.org/10.1038/s41589-019-0279-5 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Zhang, Xiaoyu
Crowley, Vincent M.
Wucherpfennig, Thomas G.
Dix, Melissa M.
Cravatt, Benjamin F.
Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
title Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
title_full Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
title_fullStr Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
title_full_unstemmed Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
title_short Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16
title_sort electrophilic protacs that degrade nuclear proteins by engaging dcaf16
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592777/
https://www.ncbi.nlm.nih.gov/pubmed/31209349
http://dx.doi.org/10.1038/s41589-019-0279-5
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