Scott, Daniel C.Hammill, Jared T.Min, JaekiRhee, DavidConnelly, MicheleSviderskiy, Vladislav O.Bhasin, DeepakChen, YizheOng, Su-SienChai, Sergio C.Goktug, Asli N.Huang, GuochangMonda, Julie K.Low, JonathanKim, Ho ShinPaulo, JoaoCannon, Joe R.Shelat, Anang A.Chen, TaoshengKelsall, Ian R.Alpi, Arno F.Pagala, VishwajeethWang, XushengPeng, JunminSingh, BhuvaneshHarper, J. WadeSchulman, Brenda A.Guy, R. Kip2018-01-182017Scott, 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.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34651810N-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.en-USJournal Article2018-01-1810.1038/nchembio.2386