E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin

Hao Huang, Derek F. Ceccarelli, Stephen Orlicky, Daniel J. St-Cyr, Amy Ziemba, Pankaj Garg, Serge Plamondon, Manfred Auer, Sachdev Sidhu, Anne Marinier, Gary Kleiger, Mike Tyers*, Frank Sicheri

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Weak protein interactions between ubiquitin and the ubiquitin-proteasome system (UPS) enzymes that mediate its covalent attachment to substrates serve to position ubiquitin for optimal catalytic transfer. We show that a small-molecule inhibitor of the E2 ubiquitin-conjugating enzyme Cdc34A, called CC0651, acts by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin-binding site. A structure of the ternary CC0651-Cdc34A-ubiquitin complex reveals that the inhibitor engages a composite binding pocket formed from Cdc34A and ubiquitin. CC0651 also suppresses the spontaneous hydrolysis rate of the Cdc34A-ubiquitin thioester without decreasing the interaction between Cdc34A and the RING domain subunit of the E3 enzyme. Stabilization of the numerous other weak interactions between ubiquitin and UPS enzymes by small molecules may be a feasible strategy to selectively inhibit different UPS activities.

Original languageEnglish
Pages (from-to)156-163
Number of pages8
JournalNature Chemical Biology
Early online date15 Dec 2013
Publication statusPublished - 1 Feb 2014

Keywords / Materials (for Non-textual outputs)

  • ring e3 ligase
  • conjugating enzyme
  • complex
  • CDC34
  • activation
  • mechanism
  • reveals
  • domain
  • SCF
  • substrate


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