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5cgj

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Revision as of 12:05, 14 June 2023

Crystal structure of murine Keap1 in complex with RA839, a non-covalent small-molecule binder to Keap1 and selective activator of Nrf2 signalling.

Structural highlights

5cgj 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.
Ligands:	,
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).^[1] ^[2]

Publication Abstract from PubMed

The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors, the activity of Nrf2 is inhibited by its interaction with the Keap1 (kelch-like ECH-associated protein 1). Here, we describe (3S)-1-[4-[(2,3,5,6-tetramethylphenyl) sulfonylamino]-1-naphthyl]pyrrolidine-3-carboxylic acid (RA839), a small molecule that binds noncovalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 mum, as demonstrated by x-ray co-crystallization and isothermal titration calorimetry. Whole genome DNA arrays showed that at 10 mum RA839 significantly regulated 105 probe sets in bone marrow-derived macrophages. Canonical pathway mapping of these probe sets revealed an activation of pathways linked with Nrf2 signaling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knock-out macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me), RA839 prevented the induction of both inducible nitric-oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice, RA839 acutely induced Nrf2 target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2.

Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling.,Winkel AF, Engel CK, Margerie D, Kannt A, Szillat H, Glombik H, Kallus C, Ruf S, Gussregen S, Riedel J, Herling AW, von Knethen A, Weigert A, Brune B, Schmoll D J Biol Chem. 2015 Nov 20;290(47):28446-55. doi: 10.1074/jbc.M115.678136. Epub, 2015 Oct 12. PMID:26459563^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999 Jan 1;13(1):76-86. PMID:9887101
↑ McMahon M, Itoh K, Yamamoto M, Hayes JD. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem. 2003 Jun 13;278(24):21592-600. Epub 2003 Apr 7. PMID:12682069 doi:10.1074/jbc.M300931200
↑ Winkel AF, Engel CK, Margerie D, Kannt A, Szillat H, Glombik H, Kallus C, Ruf S, Gussregen S, Riedel J, Herling AW, von Knethen A, Weigert A, Brune B, Schmoll D. Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling. J Biol Chem. 2015 Nov 20;290(47):28446-55. doi: 10.1074/jbc.M115.678136. Epub, 2015 Oct 12. PMID:26459563 doi:http://dx.doi.org/10.1074/jbc.M115.678136

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5cgj"

Categories: Large Structures | Mus musculus | Engel CK | Loenze P | Schimanski-Breves S

@@ Line 3: / Line 3: @@
 <StructureSection load='5cgj' size='340' side='right'caption='[[5cgj]], [[Resolution|resolution]] 3.36&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5cgj]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CGJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CGJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5cgj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CGJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CGJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=51M:(3S)-1-(4-{[(2,3,5,6-TETRAMETHYLPHENYL)SULFONYL]AMINO}NAPHTHALEN-1-YL)PYRROLIDINE-3-CARBOXYLIC+ACID'>51M</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=51M:(3S)-1-(4-{[(2,3,5,6-TETRAMETHYLPHENYL)SULFONYL]AMINO}NAPHTHALEN-1-YL)PYRROLIDINE-3-CARBOXYLIC+ACID'>51M</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Keap1, Inrf2, Kiaa0132 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5cgj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cgj OCA], [https://pdbe.org/5cgj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cgj RCSB], [https://www.ebi.ac.uk/pdbsum/5cgj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cgj ProSAT]</span></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=5cgj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cgj OCA], [http://pdbe.org/5cgj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cgj RCSB], [http://www.ebi.ac.uk/pdbsum/5cgj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5cgj ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/KEAP1_MOUSE 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).<ref>PMID:9887101</ref> <ref>PMID:12682069</ref>
+[https://www.uniprot.org/uniprot/KEAP1_MOUSE 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).<ref>PMID:9887101</ref> <ref>PMID:12682069</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 26: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Lk3 transgenic mice]]
+[[Category: Mus musculus]]
-[[Category: Engel, C K]]
+[[Category: Engel CK]]
-[[Category: Loenze, P]]
+[[Category: Loenze P]]
-[[Category: Schimanski-Breves, S]]
+[[Category: Schimanski-Breves S]]
-[[Category: Beta propeller]]
-[[Category: Complex]]
-[[Category: Inhibitor]]
-[[Category: Protein binding]]

5cgj

From Proteopedia

Revision as of 12:05, 14 June 2023

Crystal structure of murine Keap1 in complex with RA839, a non-covalent small-molecule binder to Keap1 and selective activator of Nrf2 signalling.

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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