View source for 5ibk


==Skp1-F-box in complex with a ubiquitin variant==
<StructureSection load='5ibk' size='340' side='right'caption='[[5ibk]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ibk]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IBK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IBK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.503&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ibk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ibk OCA], [https://pdbe.org/5ibk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ibk RCSB], [https://www.ebi.ac.uk/pdbsum/5ibk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ibk ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SKP1_HUMAN SKP1_HUMAN] Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(Cyclin F) directs ubiquitination of CP110.<ref>PMID:16209941</ref> <ref>PMID:20181953</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Skp1-Cul1-F-box (SCF) E3 ligases play key roles in multiple cellular processes through ubiquitination and subsequent degradation of substrate proteins. Although Skp1 and Cul1 are invariant components of all SCF complexes, the 69 different human F-box proteins are variable substrate binding modules that determine specificity. SCF E3 ligases are activated in many cancers and inhibitors could have therapeutic potential. Here, we used phage display to develop specific ubiquitin-based inhibitors against two F-box proteins, Fbw7 and Fbw11. Unexpectedly, the ubiquitin variants bind at the interface of Skp1 and F-box proteins and inhibit ligase activity by preventing Cul1 binding to the same surface. Using structure-based design and phage display, we modified the initial inhibitors to generate broad-spectrum inhibitors that targeted many SCF ligases, or conversely, a highly specific inhibitor that discriminated between even the close homologs Fbw11 and Fbw1. We propose that most F-box proteins can be targeted by this approach for basic research and for potential cancer therapies.

Inhibition of SCF ubiquitin ligases by engineered ubiquitin variants that target the Cul1 binding site on the Skp1-F-box interface.,Gorelik M, Orlicky S, Sartori MA, Tang X, Marcon E, Kurinov I, Greenblatt JF, Tyers M, Moffat J, Sicheri F, Sidhu SS Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3527-32. doi:, 10.1073/pnas.1519389113. Epub 2016 Mar 14. PMID:26976582<ref>PMID:26976582</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ibk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Orlicky S]]
[[Category: Sicheri F]]