7of9

Keap1 kelch domain bound to a small molecule fragment

spinqualitylabelsall models 7of9, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7of9 is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: DMS, VBK Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KEAP1_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). Publication Abstract from PubMed Targeting the protein-protein interaction (PPI) between the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its repressor, Kelch-like ECH-associated protein 1 (Keap1), constitutes a promising strategy for treating diseases involving oxidative stress and inflammation. Here, a fragment-based drug discovery (FBDD) campaign resulted in novel, high-affinity (Ki = 280 nM), and cell-active noncovalent small-molecule Keap1-Nrf2 PPI inhibitors. We screened 2500 fragments using orthogonal assays horizontal line fluorescence polarization (FP), thermal shift assay (TSA), and surface plasmon resonance (SPR) horizontal line and validated the hits by saturation transfer difference (STD) NMR, leading to 28 high-priority hits. Thirteen co-structures showed fragments binding mainly in the P4 and P5 subpockets of Keap1's Kelch domain, and three fluorenone-based fragments featuring a novel binding mode were optimized by structure-based drug discovery. We thereby disclose several fragment hits, including their binding modes, and show how FBDD can be performed to find new small-molecule Keap1-Nrf2 PPI inhibitors. Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery.,Narayanan D, Tran KT, Pallesen JS, Solbak SMO, Qin Y, Mukminova E, Luchini M, Vasilyeva KO, Gonzalez Chichon D, Goutsiou G, Poulsen C, Haapanen N, Popowicz GM, Sattler M, Olagnier D, Gajhede M, Bach A J Med Chem. 2022 Oct 20. doi: 10.1021/acs.jmedchem.2c00830. PMID:36263945 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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