ArticleProtein engineering, design & selection : PEDS2016
Engineering a genetically encoded competitive inhibitor of the KEAP1-NRF2 interaction via structure-based design and phage display.
Article in Protein engineering, design & selection : PEDS, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Computational design of diverse nuclear factor erythroid 2 activators with cellular antioxidative activity.iScience · 2025Article
- Modular Nanotransporters Deliver Anti-Keap1 Monobody into Mouse Hepatocytes, Thereby Inhibiting Production of Reactive Oxygen Species.Pharmaceutics · 2024Article
- Optimization of a Modular Nanotransporter Design for Targeted Intracellular Delivery of Photosensitizer.Pharmaceutics · 2024Article
- Identification of Inhibitors of the Disease-Associated Protein Phosphatase Scp1 Using Antibody Mimetic Molecules.International journal of molecular sciences · 2024Article
- Modular Nanotransporters Delivering Biologically Active Molecules to the Surface of Mitochondria.Pharmaceutics · 2023Article
- An Approach to Evaluate the Effective Cytoplasmic Concentration of Bioactive Agents Interacting with a Selected Intracellular Target Protein.Pharmaceutics · 2023Article
- Nrf2/Keap1/ARE signaling: Towards specific regulation.Life sciences · 2022Review
- FN3-based monobodies selective for the receptor binding domain of the SARS-CoV-2 spike protein.New biotechnology · 2021Article
- Exploring the binding of rationally engineered tandem-repeat proteins to E3 ubiquitin ligase Keap1.Protein engineering, design & selection : PEDS · 2021Article
- Exploring new strategies for grafting binding peptides onto protein loops using a consensus-designed tetratricopeptide repeat scaffold.Protein science : a publication of the Protein Society · 2019Article
- NRF2 Activation in Cancer: From DNA to Protein.Cancer research · 2019Review
- Ultrahigh specificity in a network of computationally designed protein-interaction pairs.Nature communications · 2018Article
- Engineering a Protein Binder Specific for p38α with Interface Expansion.Biochemistry · 2018Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
In its basal state, KEAP1 binds the transcription factor NRF2 (Kd = 5 nM) and promotes its degradation by ubiquitylation. Changes in the redox environment lead to modification of key cysteines within KEAP1, resulting in NRF2 protein accumulation and the transcription of genes important for restoring the cellular redox state. Using phage display and a computational loop grafting protocol, we engineered a monobody (R1) that is a potent competitive inhibitor of the KEAP1-NRF2 interaction. R1 bound to KEAP1 with a Kd of 300 pM and in human cells freed NRF2 from KEAP1 resulting in activation of the NRF2 promoter. Unlike cysteine-reactive small molecules that lack protein specificity, R1 is a genetically encoded, reversible inhibitor designed specifically for KEAP1. R1 should prove useful for studying the role of the KEAP1-NRF2 interaction in several disease states. The structure-based phage display strategy employed here is a general approach for engineering high-affinity binders that compete with naturally occurring interactions.
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