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| Item Type: | Preprint |
|---|---|
| Title: | Insights into therapeutic discovery through the Kelch domain structure of Keap1 at ambient temperature |
| Creators Name: | Yilmaz, M., Sever, B., Kutlu, Y., Gul, M., Okuducu, C., Tavli, S., Otsuka, M., Fujita, M., Haliloglu, T., Ciftci, H. and DeMirci, H. |
| Abstract: | The Kelch-like-ECH associated protein 1 (Keap1) is a part of the E3-ubiquitin ligase complex that binds to Nuclear factor erythroid 2-related factor 2 (Nrf2) protein and facilitates its degradation by the eukaryotic 26S proteasome. The Kelch domain of Keap1 includes six repeated structural signature motifs, approximately 45–55 amino acid residues in length. Each Kelch repeat contains highly conserved residues and is known to form one blade of beta-propeller structure. Here, we report the dimeric Kelch domain of Keap1 determined at 3.0 Å resolution at the Turkish Light Source ‘Turkish DeLight’ at ambient temperature. Our structure provides new structural dynamics information of the dimeric Keap1 Kelch domain at ambient temperature. It displays potential conformational changes of Keap1 residues, particularly at the Dimethyl fumarate (DMF) and Nrf2 binding regions, due to observed temperature shifts. Supported by the Gaussian Network Model (GNM) analysis, the dynamics of the Kelch domain revealed that the allosteric behavior of DMF binding residues is fully established in the ambient temperature structure. We also performed complementary molecular docking studies using our ambient temperature structure for numerous compounds acting as electrophilic irreversible indirect or non-covalent direct inhibitors of the Keap1/Nrf2 complex. Our data suggest that our previously reported novel compound, a hybrid of L-carnosine and L-histidyl hydrazide (CNN), revealed the most favorable scoring functions and prominent interactions with critical Keap1 residues. Collectively, our in silico and in crystallo results suggest a new potential lead compound for Keap1 inhibition. Additionally, understanding the dimeric form of the Keap1 Kelch domain and conformational changes around the DMF and Nrf2 binding sites at ambient temperature is critical for understanding Keap1-Nrf2 interaction dynamics. |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2024.07.30.605796 |
| Date: | 2 August 2024 |
| Official Publication: | https://doi.org/10.1101/2024.07.30.605796 |
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