6FFM

Crystal Structure of Human KEAP1 BTB Domain in Complex with isoxazoline-based inhibitor

Summary for 6FFM

• Entry DOI: 10.2210/pdb6ffm/pdb
• Descriptor: Kelch-like ECH-associated protein 1, ~{N}-[4-[(5~{R})-4,5-dihydro-1,2-oxazol-5-yl]phenyl]ethanamide (3 entities in total)
• Functional Keywords: 3-bromo-4 5-dihydroisoxazole, btb domain, antioxidant response, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15410.80

Authors

Moniot, S.,Steegborn, C. (deposition date: 2018-01-08, release date: 2018-11-14, Last modification date: 2024-11-20)

Primary citation

Pinto, A.,El Ali, Z.,Moniot, S.,Tamborini, L.,Steegborn, C.,Foresti, R.,De Micheli, C.
Effects of 3-Bromo-4,5-dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase-1 Expression.
ChemistryOpen, 7:858-864, 2018

PubMed Abstract: Natural and synthetic electrophilic compounds have been shown to activate the antioxidant protective Nrf2 (nuclear factor erythroid 2-related factor 2)/heme oxygenase-1 (HO-1) axis in cells and tissues. Here, we tested the ability of different isoxazoline-based electrophiles to up-regulate Nrf2/HO-1. The potency of activation is dependent on the leaving group at the 3-position of the isoxazoline nucleus, and an additional ring on the molecule limits the Nrf2/HO-1 activating properties. Among the synthetized compounds, we identified 3-bromo-5-phenyl-4,5-dihydroisoxazole as the derivative with best activating properties in THP-1 human monocytic cells. We have confirmed that the target of our compounds is the Cys151 of the BTB domain of Keap1 by using mass spectrometry analyses and X-ray crystallography. Our findings demonstrate that these compounds affect the Nrf2/HO-1 axis and highlight a positive activity that can be of relevance from a therapeutic perspective in inflammation and infection.

PubMed: 30397576
DOI: 10.1002/open.201800185

Experimental method

X-RAY DIFFRACTION (2.2 Å)