Discovery of a Kelch-like ECH-associated protein 1-inhibitory tetrapeptide and its structural characterization
Autor: | Kotaro Sakamoto, Satoshi Sogabe, Akito Kadotani, Junichi Sakamoto, Yasunori Fukuda, Yusuke Kamada |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Models Molecular Phage display NF-E2-Related Factor 2 Amino Acid Motifs Biophysics Gene Expression Biology Crystallography X-Ray Biochemistry Protein Structure Secondary Protein–protein interaction 03 medical and health sciences Protein Domains Peptide Library Consensus sequence Escherichia coli Humans Cloning Molecular Molecular Biology Transcription factor Binding Sites Kelch-Like ECH-Associated Protein 1 030102 biochemistry & molecular biology Tetrapeptide Drug discovery Cell Biology KEAP1 Recombinant Proteins Kinetics 030104 developmental biology Thermodynamics Oligopeptides Protein Binding |
Zdroj: | Biochemical and biophysical research communications. 486(3) |
ISSN: | 1090-2104 |
Popis: | Keap1 constitutively binds to the transcription factor Nrf2 to promote its degradation, resulting in negative modulation of genes involved in cellular protection against oxidative stress. Keap1 is increasingly recognized as an attractive target for treating diseases involving oxidative stress, including cancer, atherosclerosis, diabetes, arthritis, and neurodegeneration. We used phage-display peptide screening to identify a tetrapeptide showing moderate binding affinity, which inhibits the interaction between Nrf2 and Keap1. The tetrapeptide does not include an ETGE motif, which is a commonly found consensus sequence in known peptidic inhibitors. In addition to affinity parameters, IC50, KD, and thermodynamic parameters, the crystal structure of the complex was determined to elucidate the binding conformation. The binding interactions resemble those of known small-molecule inhibitors as opposed to those of substrates and peptidic inhibitors. Although the tetrapeptide's affinity is not very high, our results may help facilitate the designing of small-molecule inhibitors during lead generation in drug discovery. |
Databáze: | OpenAIRE |
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