An allosteric inhibitor of substrate recognition by the SCF[superscript Cdc4] ubiquitin ligase
- Mount Sinai Hospital
The specificity of SCF ubiquitin ligase-mediated protein degradation is determined by F-box proteins. 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 SCF{sup Cdc4}. 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.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1002627
- Journal Information:
- Nat. Biotechnol., Vol. 28, Issue (7) ; 07, 2010; ISSN 1087-0156
- Country of Publication:
- United States
- Language:
- ENGLISH
Similar Records
Composite low affinity interactions dictate recognition of the cyclin-dependent kinase inhibitor Sic1 by the SCF[superscript Cdc4] ubiquitin ligase
Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase