ArticleFEBS open bio2015
Multiple binding modes of a small molecule to human Keap1 revealed by X-ray crystallography and molecular dynamics simulation.
Article in FEBS open bio, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 33 citations in OpenAlex.
- 3,5-Dicaffeoylquinic Acid Delayed Aging and Promoted Oxidative Stress Tolerance via Activation of the SKN-1/Nrf2 Signaling Pathway.Food science & nutrition · 2026Article
- Optimization of Crystal Structures in Polylithionite Concentrate: A Molecular Dynamics Approach to Lithium Extraction Efficiency.Nanomaterials (Basel, Switzerland) · 2024Article
- KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential.Medicinal research reviews · 2023Review
- An anti-diabetic drug targets NEET (CISD) proteins through destabilization of their [2Fe-2S] clusters.Communications biology · 2022Article
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- Further thermo-stabilization of thermophilic rhodopsin from Thermus thermophilus JL-18 through engineering in extramembrane regions.Proteins · 2021Article
- Characterization of the inhibition mechanism of a tissuefactor inhibiting single-chain variable fragment: a combined computational approach.Journal of molecular modeling · 2020Article
- Article
- Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques.Molecules (Basel, Switzerland) · 2019Article
- An introduction to classical molecular dynamics simulation for experimental scattering users.Journal of applied crystallography · 2019Article
- Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.Nature reviews. Drug discovery · 2019Review
- Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review.Drug design, development and therapy · 2018Review
- Article
- Combined computational and experimental studies of molecular interactions of albuterol sulfate with bovine serum albumin for pulmonary drug nanoparticles.Drug design, development and therapy · 2016Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Keap1 protein acts as a cellular sensor for oxidative stresses and regulates the transcription level of antioxidant genes through the ubiquitination of a corresponding transcription factor, Nrf2. A small molecule capable of binding to the Nrf2 interaction site of Keap1 could be a useful medicine. Here, we report two crystal structures, referred to as the soaking and the cocrystallization forms, of the Kelch domain of Keap1 with a small molecule, Ligand1. In these two forms, the Ligand1 molecule occupied the binding site of Keap1 so as to mimic the ETGE motif of Nrf2, although the mode of binding differed in the two forms. Because the Ligand1 molecule mediated the crystal packing in both the forms, the influence of crystal packing on the ligand binding was examined using a molecular dynamics (MD) simulation in aqueous conditions. In the MD structures from the soaking form, the ligand remained bound to Keap1 for over 20 ns, whereas the ligand tended to dissociate in the cocrystallization form. The MD structures could be classified into a few clusters that were related to but distinct from the crystal structures, indicating that the binding modes observed in crystals might be atypical of those in solution. However, the dominant ligand recognition residues in the crystal structures were commonly used in the MD structures to anchor the ligand. Therefore, the present structural information together with the MD simulation will be a useful basis for pharmaceutical drug development.
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