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

Cell chemical biology 2019 Feb 21

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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. Copyright © 2018 Elsevier Ltd. All rights reserved.

Citation

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. Allosteric Inhibition of Ubiquitin-like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme. Cell chemical biology. 2019 Feb 21;26(2):278-288.e6