Academic Journal
Blocking an N-Terminal Acetylation-Dependent Protein Interaction Inhibits an E3 Ligase
| العنوان: | Blocking an N-Terminal Acetylation-Dependent Protein Interaction Inhibits an E3 Ligase |
|---|---|
| المؤلفون: | Scott, Daniel C., Hammill, Jared T., Min, Jaeki, Rhee, David Y., Connelly, Michele, Sviderskiy, Vladislav O., Bhasin, Deepak, Chen, Yizhe, Ong, Su-Sien, Chai, Sergio C., Goktug, Asli N., Huang, Guochang, Monda, Julie K., Low, Jonathan, Kim, Ho Shin, Paulo, Joao A., Cannon, Joe R., Shelat, Anang A., Chen, Taosheng, Kelsall, Ian R., Alpi, Arno F., Pagala, Vishwajeeth, Wang, Xusheng, Peng, Junmin, Singh, Bhuvanesh, Harper, J. Wade, Schulman, Brenda A., Guy, R. Kiplin |
| المصدر: | Pharmaceutical Sciences Faculty Publications |
| بيانات النشر: | UKnowledge |
| سنة النشر: | 2017 |
| المجموعة: | University of Kentucky: UKnowledge |
| مصطلحات موضوعية: | Chemical tools, Post-translational modifications, Proteins, Screening, X-ray crystallography, Acetylation, Binding Sites, Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Models, Molecular, Molecular Structure, NEDD8 Protein, Small Molecule Libraries, Structure-Activity Relationship, Ubiquitin-Protein Ligases, Ubiquitins, Amino Acids, Peptides, and Proteins, Cell and Developmental Biology, Pharmacy and Pharmaceutical Sciences |
| الوصف: | 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. |
| نوع الوثيقة: | text |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| Relation: | Structural data have been deposited in the Protein DataBank (PDB) with coordinate accession numbers 5V83.pdb (DCN1-NAcM-HIT), 5V86.pdb (DCN1-NAcM-OPT), 5V88.pdb (DCN1:NAcM-COV), 5V89.pdb (DCN4PONY:CUL1WHB). All other data generated or analyzed during this study are included in this published article (and its supplementary information files) or are available from the corresponding author on reasonable request. Supplementary information is available in the online version of the paper.; https://uknowledge.uky.edu/ps_facpub/133; https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1133&context=ps_facpub |
| الاتاحة: | https://uknowledge.uky.edu/ps_facpub/133 https://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1133&context=ps_facpub |
| رقم الانضمام: | edsbas.107D02A0 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |