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==Crystal Structure of Human KEAP1 BTB Domain in Complex with isoxazoline-based inhibitor== | |||
<StructureSection load='6ffm' size='340' side='right' caption='[[6ffm]], [[Resolution|resolution]] 2.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ffm]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FFM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FFM FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D8N:~{N}-[4-[(5~{R})-4,5-dihydro-1,2-oxazol-5-yl]phenyl]ethanamide'>D8N</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ffm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ffm OCA], [http://pdbe.org/6ffm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ffm RCSB], [http://www.ebi.ac.uk/pdbsum/6ffm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ffm ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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 1 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. | |||
Effects of 3-Bromo-4,5-dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase-1 Expression.,Pinto A, El Ali Z, Moniot S, Tamborini L, Steegborn C, Foresti R, De Micheli C ChemistryOpen. 2018 Oct 12;7(11):858-864. doi: 10.1002/open.201800185., eCollection 2018 Nov. PMID:30397576<ref>PMID:30397576</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ffm" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Moniot, S]] | [[Category: Moniot, S]] | ||
[[Category: Steegborn, C]] | [[Category: Steegborn, C]] | ||
[[Category: 3-bromo-4 5-dihydroisoxazole]] | |||
[[Category: Antioxidant response]] | |||
[[Category: Btb domain]] | |||
[[Category: Signaling protein]] | |||
Revision as of 11:19, 14 November 2018
Crystal Structure of Human KEAP1 BTB Domain in Complex with isoxazoline-based inhibitorCrystal Structure of Human KEAP1 BTB Domain in Complex with isoxazoline-based inhibitor
Structural highlights
Publication Abstract from PubMedNatural 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 1 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. Effects of 3-Bromo-4,5-dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase-1 Expression.,Pinto A, El Ali Z, Moniot S, Tamborini L, Steegborn C, Foresti R, De Micheli C ChemistryOpen. 2018 Oct 12;7(11):858-864. doi: 10.1002/open.201800185., eCollection 2018 Nov. PMID:30397576[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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