Journal
NATURE CHEMICAL BIOLOGY
Volume 13, Issue 8, Pages 850-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.2386
Keywords
-
Categories
Funding
- NCI NIH HHS [P30 CA021765] Funding Source: Medline
- NIA NIH HHS [R01 AG011085] Funding Source: Medline
- NIDDK NIH HHS [K01 DK098285] Funding Source: Medline
- NIGMS NIH HHS [F32 GM113310, R01 GM114260, R37 GM069530] Funding Source: Medline
Ask authors/readers for more resources
N-terminal acetylation is an abundant modification influencing protein functions. Because similar to 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available