5V89

Structure of DCN4 PONY domain bound to CUL1 WHB

Summary for 5V89

• Entry DOI: 10.2210/pdb5v89/pdb
• Related: 5V83 5V86 5V88
• Descriptor: DCN1-like protein 4, Cullin-1 (3 entities in total)
• Functional Keywords: e3 ligase, ligase - protein binding complex, ligase / protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 31772.53

Authors

Guy, R.K.,Schulman, B.A.,Scott, D.C.,Hammill, J.T. (deposition date: 2017-03-21, release date: 2017-05-24, Last modification date: 2023-10-04)

Primary citation

Scott, D.C.,Hammill, J.T.,Min, J.,Rhee, D.Y.,Connelly, M.,Sviderskiy, V.O.,Bhasin, D.,Chen, Y.,Ong, S.S.,Chai, S.C.,Goktug, A.N.,Huang, G.,Monda, J.K.,Low, J.,Kim, H.S.,Paulo, J.A.,Cannon, J.R.,Shelat, A.A.,Chen, T.,Kelsall, I.R.,Alpi, A.F.,Pagala, V.,Wang, X.,Peng, J.,Singh, B.,Harper, J.W.,Schulman, B.A.,Guy, R.K.
Blocking an N-terminal acetylation-dependent protein interaction inhibits an E3 ligase.
Nat. Chem. Biol., 13:850-857, 2017

PubMed 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.

PubMed: 28581483
DOI: 10.1038/nchembio.2386

Experimental method

X-RAY DIFFRACTION (1.55 Å)