8q1r
From Proteopedia
mouse Keap1 in complex with stapled peptide
Structural highlights
FunctionKEAP1_MOUSE Retains NFE2L2/NRF2 in the cytosol. Functions as substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1. Targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. May also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome (By similarity).[1] [2] Publication Abstract from PubMedThe disruption of the protein-protein interaction (PPI) between Nrf2 and Keap1 is an attractive strategy to counteract the oxidative stress that characterises a variety of severe diseases. Peptides represent a complementary approach to small molecules for the inhibition of this therapeutically important PPI. However, due to their polar nature and the negative net charge required for binding to Keap1, the peptides reported to date exhibit either mid-micromolar activity or are inactive in cells. Herein, we present a two-component peptide stapling strategy to rapidly access a variety of constrained and functionalised peptides that target the Nrf2/Keap1 PPI. The most promising peptide, P8-H containing a fatty acid tag, binds to Keap1 with nanomolar affinity and is effective at inducing transcription of ARE genes in a human lung epithelial cell line at sub-micromolar concentration. Furthermore, crystallography of the peptide in complex with Keap1 yielded a high resolution X-ray structure, adding to the toolbox of structures available to develop cell-permeable peptidomimetic inhibitors. A cell-active cyclic peptide targeting the Nrf2/Keap1 protein-protein interaction.,Iegre J, Krajcovicova S, Gunnarsson A, Wissler L, Kack H, Luchniak A, Tangefjord S, Narjes F, Spring DR Chem Sci. 2023 Sep 20;14(39):10800-10805. doi: 10.1039/d3sc04083f. eCollection , 2023 Oct 11. PMID:37829032[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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