ArticleProceedings of the National Academy of Sciences of the United States of America2016
Inhibition of SCF ubiquitin ligases by engineered ubiquitin variants that target the Cul1 binding site on the Skp1-F-box interface.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 73 citations in OpenAlex.
- Genetic Variants from Large Cohorts and Familial Studies Implicate Common Mechanisms in Schizophrenia.Biology · 2026Review
- E2 variants for probing E3 ubiquitin ligase activities.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Cul5: immune cell function and therapeutic potential.Frontiers in immunology · 2026Review
- Identification and expression profiles of tubby‑like proteins coding genes in Brassica rapa (B. rapa) in response to hormone and drought stress.BMC plant biology · 2025Article
- Effective delivery of miR-150-5p with nucleus pulposus cell-specific nanoparticles attenuates intervertebral disc degeneration.Journal of nanobiotechnology · 2024Article
- SCFBiomedicines · 2024Article
- Review
- Ubiquitin Engineering for Interrogating the Ubiquitin-Proteasome System and Novel Therapeutic Strategies.Cells · 2023Review
- The Multifaceted Role of the Ubiquitin Proteasome System in Pathogenesis and Diseases.Biomolecules · 2022Article
- On the Study of Deubiquitinases: Using the Right Tools for the Job.Biomolecules · 2022Review
- Panel of Engineered Ubiquitin Variants Targeting the Family of Human Ubiquitin Interacting Motifs.ACS chemical biology · 2022Article
- Clinical significance of FBXW7 loss of function in human cancers.Molecular cancer · 2022Review
- Targeted Degradation of 53BP1 Using Ubiquitin Variant Induced Proximity.Biomolecules · 2022Article
- Article
- Structural and functional characterization of ubiquitin variant inhibitors for the JAMM-family deubiquitinases STAMBP and STAMBPL1.The Journal of biological chemistry · 2021Article
- Targeting the Ubiquitin Signaling Cascade in Tumor Microenvironment for Cancer Therapy.International journal of molecular sciences · 2021Review
- Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance.Redox biology · 2020Article
- [Targeting Cullin-RING E3 ligases for anti-cancer therapy: efforts on drug discovery].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2020Review
- The role of E3 ubiquitin ligase HECTD3 in cancer and beyond.Cellular and molecular life sciences : CMLS · 2020Review
- Protein Engineering in the Ubiquitin System: Tools for Discovery and Beyond.Pharmacological reviews · 2020Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.