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

Daniel C. Scott, Jared T. Hammill, Jaeki Min, David Y. Rhee, Michele C. Connelly, Vladislav O. Sviderskiy, Deepak Bhasin, Yizhe Chen, Su-Sien Ong, Sergio C. Chai, Asli N. Goktug, Guochang Huang, Julie K. Monda, Jonathan Low, Ho Shin Kim, Joao A. Paulo, Joe R. Cannon, Anang A. Shelat, Taosheng Chen, Ian R. KelsallArno F. Alpi, Vishwajeeth Pagala, Xusheng Wang, Junmin Peng, Bhuvanesh Singh, J. Wade Harper, Brenda A. Schulman (Lead / Corresponding author), R. Kip Guy (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)850-857
Number of pages8
JournalNature Chemical Biology
Issue number8
Early online date5 Jun 2017
Publication statusPublished - Jun 2017


  • Journal article
  • Chemical tools
  • Post-translational modifications
  • Proteins
  • Screening
  • X-ray crystallography


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