An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme

Derek F. Ceccarelli, Xiaojing Tang, Benoit Pelletier, Stephen Orlicky, Weilin Xie, Veronique Plantevin, Dante Neculai, Yang-Chieh Chou, Abiodun Ogunjimi, Abdallah Al-Hakim, Xaralabos Varelas, Joanna Koszela, Gregory A. Wasney, Masoud Vedadi, Sirano Dhe-Paganon, Sarah Cox, Shuichan Xu, Antonia Lopez-Girona, Frank Mercurio, Jeff WranaDaniel Durocher, Sylvain Meloche, David R. Webb*, Mike Tyers, Frank Sicheri

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 that selectively inhibits hCdc34. Structure determination revealed that CC0651 inserts into a cryptic binding pocket on hCdc34 distant from the catalytic site, causing subtle but wholesale displacement of E2 secondary structural elements. CC0651 analogs inhibited proliferation of human cancer cell lines and caused accumulation of the SCFSkp2 substrate p27(Kip1). CC0651 does not affect hCdc34 interactions with E1 or E3 enzymes or the formation of the ubiquitin thioester but instead interferes with the discharge of ubiquitin to acceptor lysine residues. E2 enzymes are thus susceptible to noncatalytic site inhibition and may represent a viable class of drug target in the UPS.

Original languageEnglish
Pages (from-to)1075-1087
Number of pages13
JournalCell
Volume145
Issue number7
DOIs
Publication statusPublished - 24 Jun 2011

Keywords

  • ACTIVATION
  • P27(KIP1)
  • COMPLEX
  • CELL-DIVISION
  • E2
  • F-BOX PROTEINS
  • PROTEOLYSIS
  • LIGASE
  • PROTEASOME SYSTEM
  • SUBSTRATE

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