Allosteric Inhibition of Ubiquitin-like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme. Issue 2 (21st February 2019) - Li, Yi-Jia
Summary: 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. Graphical Abstract: Highlights: We identified an allosteric inhibitory site for an activating enzyme The lead compound inhibits the ATP-dependent step of SUMO E1 catalysis The compound has specificity to 1 out of 18 non-disulfide bonded Cys residues The compound increased miR-34b and reduced c-Myc in cellular and xenograft models Abstract : Ubiquitin-like (Ubl) post-translational modifications are potential targets for developing novel therapeutics for life-threatening diseases. Here, we have identified a new allosteric, covalent inhibitory site for inhibiting an activating enzyme of Ubl. This finding could spur innovative drug discovery efforts targeting Ubl modifications.