Allosteric Inhibition of Ubiquitin-like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme

Yi-Jia Li, Li Du, Jianghai Wang, Ramir Vega, Terry D. Lee, Yunan Miao, Grace Aldana-Masangkay, Eric R. Samuels, Baozong Li, S. Xiaohu Ouyang, Sharon A. Colayco, Ekaterina V. Bobkova, Daniela B. Divlianska, Eduard Sergienko, Thomas D.Y. Chung, Marwan Fakih, Yuan Chen

Cell Chemical Biology, 2019
DOI: 10.1016/j.chembiol.2018.10.026

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.