5IBK

Skp1-F-box in complex with a ubiquitin variant

Summary for 5IBK

• Entry DOI: 10.2210/pdb5ibk/pdb
• Descriptor: S-phase kinase-associated protein 1,S-phase kinase-associated protein 1, F-box/WD repeat-containing protein 7, Polyubiquitin-B, ... (4 entities in total)
• Functional Keywords: phage display, scf inhibitors, fbxw7, fbxw11, ?-trcp, ubiquitin, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 66612.28

Authors

Orlicky, S.,Sicheri, F. (deposition date: 2016-02-22, release date: 2016-03-30, Last modification date: 2023-09-27)

Primary citation

Gorelik, M.,Orlicky, S.,Sartori, M.A.,Tang, X.,Marcon, E.,Kurinov, I.,Greenblatt, J.F.,Tyers, M.,Moffat, J.,Sicheri, F.,Sidhu, S.S.
Inhibition of SCF ubiquitin ligases by engineered ubiquitin variants that target the Cul1 binding site on the Skp1-F-box interface.
Proc.Natl.Acad.Sci.USA, 113:3527-3532, 2016

PubMed Abstract: 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.

PubMed: 26976582
DOI: 10.1073/pnas.1519389113

Experimental method

X-RAY DIFFRACTION (2.503 Å)