AI Article Synopsis
- Researchers discovered a new allosteric inhibitory site on the SUMO-activating enzyme (E1) that could lead to potential cancer therapies targeting Ubiquitin-like (Ubl) post-translational modifications.
- This inhibitor not only reduces the activity of SUMO E1 but also supports its degradation in living organisms, likely due to changes in the enzyme's shape caused by the compound.
- The lead compound also promotes the expression of miR-34b and decreases c-Myc levels in specific cancer cell lines and mouse models, marking a significant step in developing treatments that manipulate Ubl modifications.
Article 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.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524651 | PMC |
| http://dx.doi.org/10.1016/j.chembiol.2018.10.026 | DOI Listing |
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