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Allosteric Inhibition of Ubiquitin-like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme.
Li, Yi-Jia; Du, Li; Wang, Jianghai; Vega, Ramir; Lee, Terry D; Miao, Yunan; Aldana-Masangkay, Grace; Samuels, Eric R; Li, Baozong; Ouyang, S Xiaohu; Colayco, Sharon A; Bobkova, Ekaterina V; Divlianska, Daniela B; Sergienko, Eduard; Chung, Thomas D Y; Fakih, Marwan; Chen, Yuan.
Affiliation
  • Li YJ; Department of Molecular Medicine, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • Du L; Department of Molecular Medicine, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • Wang J; Department of Molecular Medicine, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • Vega R; Department of Molecular Medicine, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • Lee TD; Department of Immunology, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA; Irell and Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA, USA.
  • Miao Y; Department of Immunology, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA; Irell and Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA, USA.
  • Aldana-Masangkay G; Department of Molecular Medicine, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • Samuels ER; Department of Molecular Medicine, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • Li B; Department of Molecular Medicine, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • Ouyang SX; SUMO Biosciences, Inc., 2265 E Foothill Boulevard, Pasadena, CA 91107, USA.
  • Colayco SA; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • Bobkova EV; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • Divlianska DB; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • Sergienko E; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • Chung TDY; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • Fakih M; Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
  • Chen Y; Department of Molecular Medicine, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA; Irell and Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA, USA. Electronic address: ychen@coh.org.
Cell Chem Biol ; 26(2): 278-288.e6, 2019 02 21.
Article in En | MEDLINE | ID: mdl-30581133
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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Full text: 1 Database: MEDLINE Main subject: Ubiquitin-Activating Enzymes / Sumoylation Type of study: Prognostic_studies Limits: Animals / Humans Language: En Year: 2019 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Ubiquitin-Activating Enzymes / Sumoylation Type of study: Prognostic_studies Limits: Animals / Humans Language: En Year: 2019 Type: Article