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Structural insights into the multiple binding modes of Dimethyl Fumarate (DMF) and its analogs to the Kelch domain of Keap1.

Unni S, Deshmukh P, Krishnappa G, Kommu P, Padmanabhan B
FEBS J 288 1599-1613 (2021)
Related entries: 6lrz, 7c5e

Cited: 20 times
EuropePMC logo PMID: 32672401

Abstract

The activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription function has been implicated in the protection of neurodegenerative diseases. The cytoplasmic protein, Kelch-like ECH-associated protein 1 (Keap1), negatively regulates Nrf2. The Keap1-Nrf2 pathway is a potential therapeutic target for tackling free-radical damage. Dimethyl fumarate (DMF) is currently an approved drug for the treatment of relapsing multiple sclerosis. Recent studies showed that DMF modifies the reactive cysteines in the BTB domain of Keap1 and thus activates Nrf2 transcription function. Intriguingly, our crystal structure studies revealed that DMF also binds to the β-propeller domain (Keap1-DC) of Keap1. The crystal structure of the complex, refined to 1.54 Å resolution, revealed unexpected features: DMF binds (a) to the Nrf2-binding site (bottom region of Keap1-DC, site 1) with moderate interaction, and (b) to the top region of Keap1-DC, near to the blade II (site 2). The specificity of the binding 'site 2' was found to be unique to blade II of the β-propeller domain. The newly identified 'site 2' region in Keap1-DC may have a different functional role to regulate Nrf2. Moreover, the crystal structures of Keap1-DC in complex with the DMF analogs, including monoethyl fumarate, fumarate, and itaconate, also exhibited similar binding modes with Keap1-DC. Binding studies confirmed that DMF binds, in a nanomolar range, to the Keap1-DC region as well as the BTB domain of Keap1. Furthermore, the competitive binding assay in the presence of the Nrf2 peptide affirmed the direct binding of DMF at the Nrf2-binding region of Keap1-DC. Overall, our studies suggest that the drug molecule, DMF, binds at multiple sites of Keap1 and thus potentially activates Nrf2 function through covalent as well as the noncovalent mode of action, to combat oxidative stress. DATABASE: Structural data are available in RCSB-protein data bank database(s) under the accession numbers 6LRZ, 7C60, and 7C5E.

Articles - 7c60 mentioned but not cited (2)

  1. Structural insights into the multiple binding modes of Dimethyl Fumarate (DMF) and its analogs to the Kelch domain of Keap1. Unni S, Deshmukh P, Krishnappa G, Kommu P, Padmanabhan B. FEBS J 288 1599-1613 (2021)
  2. In Vivo and In Silico Studies of the Hepatoprotective Activity of Tert-Butylhydroquinone. Aldaba-Muruato LR, Sánchez-Barbosa S, Rodríguez-Purata VH, Cabrera-Cruz G, Rosales-Domínguez E, Martínez-Valentín D, Alarcón-López YA, Aguirre-Vidal P, Hernández-Serda MA, Cárdenas-Granados LA, Vázquez-Valadez VH, Angeles E, Macías-Pérez JR. Int J Mol Sci 25 475 (2023)


Reviews citing this publication (8)

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  3. Nanotechnology-Based Drug Delivery to Improve the Therapeutic Benefits of NRF2 Modulators in Cancer Therapy. Sezgin-Bayindir Z, Losada-Barreiro S, Bravo-Díaz C, Sova M, Kristl J, Saso L. Antioxidants (Basel) 10 685 (2021)
  4. Nrf2: An all-rounder in depression. Zuo C, Cao H, Song Y, Gu Z, Huang Y, Yang Y, Miao J, Zhu L, Chen J, Jiang Y, Wang F. Redox Biol 58 102522 (2022)
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  7. Kelch-like proteins in the gastrointestinal tumors. Fu AB, Xiang SF, He QJ, Ying MD. Acta Pharmacol Sin 44 931-939 (2023)
  8. Dimethyl Fumarate and Intestine: From Main Suspect to Potential Ally against Gut Disorders. Manai F, Zanoletti L, Arfini D, Micco SG, Gjyzeli A, Comincini S, Amadio M. Int J Mol Sci 24 9912 (2023)

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  2. Revealing the therapeutic targets and molecular mechanisms of emodin-treated coronavirus disease 2019 via a systematic study of network pharmacology. Du HX, Zhu JQ, Chen J, Zhou HF, Yang JH, Wan HT. Aging (Albany NY) 13 14571-14589 (2021)
  3. Neuroprotective effects of dimethyl fumarate against depression-like behaviors via astrocytes and microglia modulation in mice: possible involvement of the HCAR2/Nrf2 signaling pathway. de Souza AG, Lopes IS, Filho AJMC, Cavalcante TMB, Oliveira JVS, de Carvalho MAJ, de Lima KA, Jucá PM, Mendonça SS, Mottin M, Andrade CH, de Sousa FCF, Macedo DS, de França Fonteles MM. Naunyn Schmiedebergs Arch Pharmacol 395 1029-1045 (2022)
  4. Natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase. Li W, Liao LP, Song N, Liu YJ, Ding YL, Zhang YY, Zhou XR, Sun ZY, Xiao SH, Wang HB, Lu J, Zhang NX, Jiang HL, Chen KX, Liu CP, Zheng J, Zhao KH, Luo C. Acta Pharmacol Sin 43 470-482 (2022)
  5. A potent phosphodiester Keap1-Nrf2 protein-protein interaction inhibitor as the efficient treatment of Alzheimer's disease. Sun Y, Xu L, Zheng D, Wang J, Liu G, Mo Z, Liu C, Zhang W, Yu J, Xing C, He L, Zhuang C. Redox Biol 64 102793 (2023)
  6. Adenylosuccinic Acid: An Orphan Drug with Untapped Potential. Rybalka E, Kourakis S, Bonsett CA, Moghadaszadeh B, Beggs AH, Timpani CA. Pharmaceuticals (Basel) 16 822 (2023)
  7. Hepatoprotective Activity of Lignin-Derived Polyphenols Dereplicated Using High-Resolution Mass Spectrometry, In Vivo Experiments, and Deep Learning. Orlov A, Semenov S, Rukhovich G, Sarycheva A, Kovaleva O, Semenov A, Ermakova E, Gubareva E, Bugrova AE, Kononikhin A, Fedoros EI, Nikolaev E, Zherebker A. Int J Mol Sci 23 16025 (2022)
  8. Monitoring Nrf2/ARE Pathway Activity with a New Zebrafish Reporter System. Badenetti L, Manzoli R, Rubin M, Cozza G, Moro E. Int J Mol Sci 24 6804 (2023)
  9. Synthesis and cellular evaluation of click-chemistry probes to study the biological effects of alpha, beta-unsaturated carbonyls. Morozzi C, Sauerland M, Gamon LF, Manandhar A, Ulven T, Davies MJ. Redox Biol 52 102299 (2022)
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