7X4X

BTB domain of KEAP1 in complex with MEF

Summary for 7X4X

• Entry DOI: 10.2210/pdb7x4x/pdb
• Descriptor: Kelch-like ECH-associated protein 1, 4-ethoxy-4-oxobutanoic acid (2 entities in total)
• Functional Keywords: keap1, mef, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 93935.91

Authors

Qu, L.Z. (deposition date: 2022-03-03, release date: 2023-03-08, Last modification date: 2024-11-20)

Primary citation

Qu, L.,Guo, M.,Zhang, H.,Chen, X.,Wei, H.,Jiang, L.,Li, J.,Chen, Z.,Dai, S.,Chen, Y.
Characterization of the modification of Kelch-like ECH-associated protein 1 by different fumarates.
Biochem.Biophys.Res.Commun., 605:9-15, 2022

PubMed Abstract: Fumarates (fumaric acid esters), primarily dimethyl fumarate (DMF) and monoethyl fumarate (MEF) and its salts, are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. It is widely believed that the pharmaceutical activities of fumarates are exerted through the Keap1-Nrf2 pathway. Although it has been revealed that DMF and MEF differentially modify specific Keap1 cysteine residues and result in the differential activation of Nrf2, how the modification of DMF and MEF impacts the biochemical properties of Keap1 has not been well characterized. Here, we found that both DMF and MEF can only modify the BTB domain of Keap1 and that only C151 is accessible for covalent binding in vitro. Dynamic fluorescence scanning (DSF) assays showed that the modification of DMF to Keap1 BTB increased its thermal stability, while the modification of MEF dramatically decreased its thermal stability. Further crystal structures revealed no significant conformational variation between the DMF-modified and MEF-modified BTBs. Overall, our biochemical and structural study provides a better understanding of the covalent modification of fumarates to Keap1 and may suggest fundamentally different mechanisms adopted by fumarates in regulating the Keap1-Nrf2 pathway.

PubMed: 35306364
DOI: 10.1016/j.bbrc.2022.03.059

Experimental method

X-RAY DIFFRACTION (2.96 Å)