An allosteric inhibitor of substrate recognition by the SCFCdc4 ubiquitin ligase

Stephen Orlicky, Xiaojing Tang, Victor Neduva, Nadine Elowe, Eric D. Brown, Frank Sicheri, Mike Tyers

Research output: Contribution to journalArticlepeer-review


The specificity of SCF ubiquitin ligase-mediated protein degradation is determined by F-box proteins(1,2). We identified a biplanar dicarboxylic acid compound, called SCF-I2, as an inhibitor of substrate recognition by the yeast F-box protein Cdc4 using a fluorescence polarization screen to monitor the displacement of a fluorescein-labeled phosphodegron peptide. SCF-I2 inhibits the binding and ubiquitination of full-length phosphorylated substrates by SCFCdc4. A co-crystal structure reveals that SCF-I2 inserts itself between the beta-strands of blades 5 and 6 of the WD40 propeller domain of Cdc4 at a site that is 25 angstrom away from the substrate binding site. Long-range transmission of SCF-I2 interactions distorts the substrate binding pocket and impedes recognition of key determinants in the Cdc4 phosphodegron. Mutation of the SCF-I2 binding site abrogates its inhibitory effect and explains specificity in the allosteric inhibition mechanism. Mammalian WD40 domain proteins may exhibit similar allosteric responsiveness and hence represent an extensive class of druggable target.

Original languageEnglish
Pages (from-to)733-U1743
Number of pages6
JournalNature Biotechnology
Issue number7
Early online date27 Jun 2010
Publication statusPublished - 31 Jul 2010


  • Enzyme mechanisms
  • Small molecules
  • Structural biology
  • Ubiquitin ligases


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