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

Nat Chem Biol. 2017 Aug;13(8):850-857. doi: 10.1038/nchembio.2386. Epub 2017 Jun 5.


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.

MeSH terms

  • Acetylation / drug effects
  • Binding Sites
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • NEDD8 Protein
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Ubiquitin-Protein Ligases / antagonists & inhibitors*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitins / metabolism*


  • Enzyme Inhibitors
  • NEDD8 Protein
  • NEDD8 protein, human
  • Small Molecule Libraries
  • Ubiquitins
  • Ubiquitin-Protein Ligases

Associated data

  • PubChem-Substance/336287076
  • PubChem-Substance/336287087
  • PubChem-Substance/336287092
  • PubChem-Substance/336287093
  • PubChem-Substance/336287094
  • PubChem-Substance/336287095
  • PubChem-Substance/336287096
  • PubChem-Substance/336287097
  • PubChem-Substance/336287098
  • PubChem-Substance/336287077
  • PubChem-Substance/336287078
  • PubChem-Substance/336287079
  • PubChem-Substance/336287080
  • PubChem-Substance/336287081
  • PubChem-Substance/336287082
  • PubChem-Substance/336287083
  • PubChem-Substance/336287084
  • PubChem-Substance/336287085
  • PubChem-Substance/336287086
  • PubChem-Substance/336287088
  • PubChem-Substance/336287089
  • PubChem-Substance/336287090
  • PubChem-Substance/336287091