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

Scott, D. C., Hammill, J. T., Min, J., Rhee, D. Y., Connelly, M., Sviderskiy, V. O., 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.

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 Creators:
Scott, Daniel C.1, Author
Hammill, Jared T.1, Author
Min, Jaeki1, Author
Rhee, David Y.1, Author
Connelly, Michele1, Author
Sviderskiy, Vladislav O.1, Author
Bhasin, Deepak1, Author
Chen, Yizhe1, Author
Ong, Su-Sien1, Author
Chai, Sergio C.1, Author
Goktug, Asli N.1, Author
Huang, Guochang1, Author
Monda, Julie K.1, Author
Low, Jonathan1, Author
Kim, Ho Shin1, Author
Paulo, Joao A.1, Author
Cannon, Joe R.1, Author
Shelat, Anang A.1, Author
Chen, Taosheng1, Author
Kelsall, Ian R.1, Author
Alpi, Arno F.2, Author              Pagala, Vishwajeeth1, AuthorWang, Xusheng1, AuthorPeng, Junmin1, AuthorSingh, Bhuvanesh1, AuthorHarper, J. Wade1, AuthorSchulman, Brenda A.1, AuthorGuy, R. Kip1, Author more..
Affiliations:
1external, ou_persistent22              
2Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society, ou_2466699              

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Free keywords: CULLIN NEDDYLATION; SCREENING LIBRARIES; MASS-SPECTROMETRY; CELLULAR-PROTEINS; UBIQUITIN LIGASES; NEDD8; ACETYLTRANSFERASE; FAMILY; INTERFERENCE; MECHANISMBiochemistry & Molecular Biology;
 Abstract: 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.

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Language(s): eng - English
 Dates: 2017-06-052017-08
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000405819300012
DOI: 10.1038/nchembio.2386
 Degree: -

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Title: Nature Chemical Biology
  Other : Nat. Chem. Biol.
Source Genre: Journal
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Publ. Info: New York, NY : Nature Pub. Group
Pages: - Volume / Issue: 13 (8) Sequence Number: - Start / End Page: 850 - 857 Identifier: ISSN: 1552-4450
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000021290_1