Suramin inhibits cullin-RING E3 ubiquitin ligases

Kenneth Wu, Robert A. Chong, Qing Yu, Jin Bai, Donald E. Spratt, Kevin Ching, Chan Lee, Haibin Miao, Inger Tappin, Jerard Hurwitz, Ning Zheng, Gary S. Shaw, Yi Sun, Dan P. Felsenfeld, Roberto Sanchez, Jun Nian Zheng, Zhen Qiang Pan

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43 Scopus citations


Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity is the recruitment of the E2 ubiquitin-conjugating enzyme Cdc34 through electrostatic interactions between E3?s cullin conserved basic canyon and the acidic C terminus of the E2 enzyme. This report demonstrates that a smallmolecule compound, suramin, can inhibit CRL activity by disrupting its ability to recruit Cdc34. Suramin, an antitrypansomal drug that also possesses antitumor activity, was identified here through a fluorescence-based high-throughput screen as an inhibitor of ubiquitination. Suramin was shown to target cullin 1's conserved basic canyon and to block its binding to Cdc34. Suramin inhibits the activity of a variety of CRL complexes containing cullin 2, 3, and 4A. When introduced into cells, suramin induced accumulation of CRL substrates. These observations help develop a strategy of regulating ubiquitination by targeting an E2-E3 interface through small-molecule modulators.

Original languageEnglish
Pages (from-to)E2011-E2018
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
StatePublished - 5 Apr 2016


  • E2 enzyme
  • E3 ligase
  • K48-polyubiquitination
  • Protein degradation
  • Suramin


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