Article ; Online: Allosteric Inhibition of Ubiquitin-like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme.
Cell chemical biology
2018 Volume 26, Issue 2, Page(s) 278–288.e6
Abstract: Ubiquitin-like (Ubl) post-translational modifications are potential targets for therapeutics. However, the only known mechanism for inhibiting a Ubl-activating enzyme is through targeting its ATP-binding site. Here we identify an allosteric inhibitory ... ...
| Abstract | Ubiquitin-like (Ubl) post-translational modifications are potential targets for therapeutics. However, the only known mechanism for inhibiting a Ubl-activating enzyme is through targeting its ATP-binding site. Here we identify an allosteric inhibitory site in the small ubiquitin-like modifier (SUMO)-activating enzyme (E1). This site was unexpected because both it and analogous sites are deeply buried in all previously solved structures of E1s of ubiquitin-like modifiers (Ubl). The inhibitor not only suppresses SUMO E1 activity, but also enhances its degradation in vivo, presumably due to a conformational change induced by the compound. In addition, the lead compound increased the expression of miR-34b and reduced c-Myc levels in lymphoma and colorectal cancer cell lines and a colorectal cancer xenograft mouse model. Identification of this first-in-class inhibitor of SUMO E1 is a major advance in modulating Ubl modifications for therapeutic aims. |
|---|---|
| MeSH term(s) | Allosteric Regulation ; Allosteric Site ; Animals ; Cell Line, Tumor ; High-Throughput Screening Assays ; Humans ; Mice ; Mice, SCID ; MicroRNAs/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Sumoylation/drug effects ; Transplantation, Heterologous ; Ubiquitin/metabolism ; Ubiquitin-Activating Enzymes/antagonists & inhibitors ; Ubiquitin-Activating Enzymes/metabolism ; Ubiquitination/drug effects |
| Chemical Substances | MIRN34 microRNA, human ; MicroRNAs ; Proto-Oncogene Proteins c-myc ; Small Molecule Libraries ; Ubiquitin ; Ubiquitin-Activating Enzymes (EC 6.2.1.45) |
| Language | English |
| Publishing date | 2018-12-20 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. |
| ISSN | 2451-9448 |
| ISSN (online) | 2451-9448 |
| DOI | 10.1016/j.chembiol.2018.10.026 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
Full text online
More links
Kategorien
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.
Inter-library loan at ZB MED
Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.