3mks
From Proteopedia
Crystal Structure of yeast Cdc4/Skp1 in complex with an allosteric inhibitor SCF-I2
Structural highlights
FunctionSKP1_YEAST Essential component of the E3 ubiquitin ligase complex SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins like phosphorylated SIC1. Participates in the attachment of chromosomes to the spindle. Acts as a regulatory component of the centromere DNA-binding protein complex CBF3, which is essential for chromosome segregation and movement of centromeres along microtubules. CBF3 is required for the recruitment of other kinetochore complexes to CEN DNA. It plays a role in the attachment of chromosomes to the spindle and binds selectively to a highly conserved DNA sequence called CDEIII, found in centromeres and in several promoters. The association of CBF3C with CBF3D and SGT1 is required for CBF3C activation and CBF3 assembly. SKP1/CBF3D could retrieve cyclins or cyclin-CDK-like proteins into the kinetochore thus providing cell cycle-regulated kinetochore activity. Involved in the regulation of methionine biosynthesis genes. Facilitates association of CDC53 with CDC4 and of ROY1 with YPT52.[1] [2] [3] [4] [5] [6] [7] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe 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(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 A 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. An allosteric inhibitor of substrate recognition by the SCF(Cdc4) ubiquitin ligase.,Orlicky S, Tang X, Neduva V, Elowe N, Brown ED, Sicheri F, Tyers M Nat Biotechnol. 2010 Jul;28(7):733-7. Epub 2010 Jun 27. PMID:20581844[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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