View source for 5fnt


==Structure of the Keap1 Kelch domain in complex with a small molecule inhibitor.==
<StructureSection load='5fnt' size='340' side='right'caption='[[5fnt]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5fnt]] 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=5FNT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FNT FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.79&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0PL:(3S)-3-{4-CHLORO-3-[(N-METHYLBENZENESULFONAMIDO)+METHYL]PHENYL}-3-(1-METHYL-1H-1,2,3-BENZOTRIAZOL-5-YL)PROPANOIC+ACID'>0PL</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></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=5fnt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fnt OCA], [https://pdbe.org/5fnt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fnt RCSB], [https://www.ebi.ac.uk/pdbsum/5fnt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fnt ProSAT]</span></td></tr>
</table>
== Function ==
[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 ==
KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.

Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery.,Davies TG, Wixted WE, Coyle JE, Griffiths-Jones C, Hearn K, McMenamin R, Norton D, Rich SJ, Richardson C, Saxty G, Willems HM, Woolford AJ, Cottom JE, Kou JP, Yonchuk JG, Feldser HG, Sanchez Y, Foley JP, Bolognese BJ, Logan G, Podolin PL, Yan H, Callahan JF, Heightman TD, Kerns JK J Med Chem. 2016 Apr 28;59(8):3991-4006. doi: 10.1021/acs.jmedchem.6b00228. Epub , 2016 Apr 12. PMID:27031670<ref>PMID:27031670</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5fnt" style="background-color:#fffaf0;"></div>

==See Also==
*[[Kelch-like protein 3D structures|Kelch-like protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Bolognese BJ]]
[[Category: Callahan JF]]
[[Category: Cottom JE]]
[[Category: Coyle JE]]
[[Category: Davies TG]]
[[Category: Feldser HG]]
[[Category: Foley JP]]
[[Category: Griffiths-Jones C]]
[[Category: Hearn K]]
[[Category: Heightman TD]]
[[Category: Kerns JK]]
[[Category: Kou J]]
[[Category: Logan G]]
[[Category: McMenamin R]]
[[Category: Norton D]]
[[Category: Podolin PL]]
[[Category: Rich SJ]]
[[Category: Richardson C]]
[[Category: Sanchez Y]]
[[Category: Saxty G]]
[[Category: Willems HMG]]
[[Category: Wixted WE]]
[[Category: Woolford AJ]]
[[Category: Yan H]]
[[Category: Yonchuk JG]]