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.
MeSH terms
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Acetylation / drug effects
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Binding Sites
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Models, Molecular
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Molecular Structure
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NEDD8 Protein
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Ubiquitin-Protein Ligases / antagonists & inhibitors*
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitins / metabolism*
Substances
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Enzyme Inhibitors
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NEDD8 Protein
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NEDD8 protein, human
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Small Molecule Libraries
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Ubiquitins
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Ubiquitin-Protein Ligases
Associated data
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PubChem-Substance/336287076
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PubChem-Substance/336287087
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PubChem-Substance/336287092
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PubChem-Substance/336287093
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PubChem-Substance/336287094
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PubChem-Substance/336287095
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PubChem-Substance/336287096
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PubChem-Substance/336287097
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PubChem-Substance/336287098
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PubChem-Substance/336287077
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PubChem-Substance/336287078
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PubChem-Substance/336287079
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PubChem-Substance/336287080
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PubChem-Substance/336287081
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PubChem-Substance/336287082
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PubChem-Substance/336287083
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PubChem-Substance/336287084
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PubChem-Substance/336287085
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PubChem-Substance/336287086
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PubChem-Substance/336287088
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PubChem-Substance/336287089
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PubChem-Substance/336287090
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PubChem-Substance/336287091