Blocking an N-terminal acetylation-dependent protein interaction inhibits an E3 ligase Journal Article
| Authors: | Scott, D. C.; Hammill, J. T.; Min, J.; Rhee, D. Y.; Connelly, M.; Sviderskiy, V. O.; Bhasin, D.; Chen, Y.; Ong, S. S.; Chai, S. C.; Goktug, A. N.; Huang, G.; Monda, J. K.; Low, J.; Kim, H. S.; Paulo, J. A.; Cannon, J. R.; Shelat, A. A.; Chen, T.; Kelsall, I. R.; Alpi, A. F.; Pagala, V.; Wang, X.; Peng, J.; Singh, B.; Harper, J. W.; Schulman, B. A.; Guy, R. K. |
| Article Title: | Blocking an N-terminal acetylation-dependent protein interaction inhibits an E3 ligase |
| Abstract: | N-terminal acetylation is an abundant modification influencing protein functions. Because ∼80% of mammalian cytosolic proteins are N-terminally acetylated, this modification is potentially an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N-terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions; hence, this modification may be a druggable target. We report the development of chemical probes targeting the N-terminal acetylation-dependent interaction between an E2 conjugating enzyme (UBE2M or UBC12) and DCN1 (DCUN1D1), a subunit of a multiprotein E3 ligase for the ubiquitin-like protein NEDD8. The inhibitors are highly selective with respect to other protein acetyl-amide-binding sites, inhibit NEDD8 ligation in vitro and in cells, and suppress anchorage-independent growth of a cell line with DCN1 amplification. Overall, our data demonstrate that N-terminal acetyl-dependent protein interactions are druggable targets and provide insights into targeting multiprotein E2-E3 ligases. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. |
| Keywords: | unclassified drug; human cell; dose response; ubiquitin; metabolism; ubiquitin protein ligase; protein interaction; in vitro study; dose-response relationship, drug; enzyme inhibitor; molecular library; small molecule libraries; structure activity relation; structure-activity relationship; chemistry; amino terminal sequence; enzyme inhibitors; fluorescence resonance energy transfer; binding site; hydrogen bond; models, molecular; isoleucine; threonine; binding sites; chemical structure; molecular structure; alanine; leucine; ubiquitin protein ligase e3; ubiquitin-protein ligases; glycine; molecular model; binding competition; valine; pharmacology; acetylation; ubiquitins; ubiquitin protein ligase e2; neddylation; protein acetylation; drug effects; nedd8 protein; humans; human; priority journal; article; antagonists and inhibitors; dcn1 protein; dcn2 protein; dcn3 protein; dcn4 protein; ube2m protein; nedd8 protein, human; hcc95 cell line |
| Journal Title: | Nature Chemical Biology |
| Volume: | 13 |
| Issue: | 8 |
| ISSN: | 1552-4450 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2017-08-01 |
| Start Page: | 850 |
| End Page: | 857 |
| Language: | English |
| DOI: | 10.1038/nchembio.2386 |
| PUBMED: | 28581483 |
| PROVIDER: | scopus |
| PMCID: | PMC5577376 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 October 2017 -- Source: Scopus |
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