Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase

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Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase

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Title: Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase
Author: Scott, Daniel C.; Hammill, Jared T.; Min, Jaeki; Rhee, David Y.; Connelly, Michele; Sviderskiy, Vladislav O.; Bhasin, Deepak; Chen, Yizhe; Ong, Su-Sien; Chai, Sergio C.; Goktug, Asli N.; Huang, Guochang; Monda, Julie K.; Low, Jonathan; Kim, Ho Shin; Paulo, Joao A.; Cannon, Joe R.; Shelat, Anang A.; Chen, Taosheng; Kelsall, Ian R.; Alpi, Arno F.; Pagala, Vishwajeeth; Wang, Xusheng; Peng, Junmin; Singh, Bhuvanesh; Harper, J. Wade; Schulman, Brenda A.; Guy, R. Kip

Note: Order does not necessarily reflect citation order of authors.

Citation: Scott, D. C., J. T. Hammill, J. Min, D. Y. Rhee, M. Connelly, V. O. Sviderskiy, D. Bhasin, et al. 2017. “Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase.” Nature chemical biology 13 (8): 850-857. doi:10.1038/nchembio.2386. http://dx.doi.org/10.1038/nchembio.2386.
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Abstract: N-terminal acetylation is an abundant modification influencing protein functions. Since ≈80% of mammalian cytosolic proteins are N-terminally acetylated, this potentially represents 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, suggesting it 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, aka UBC12) and DCN1 (aka 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 the anchorage-independent growth of a cell line harboring DCN1 amplification. Overall, the data demonstrate that N-terminal acetyl-dependent protein interactions are druggable targets, and provide insights into targeting multiprotein E2–E3 ligases.
Published Version: doi:10.1038/nchembio.2386
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577376/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:34651810
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