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==Crystal structure of cpd 15 bound to Keap1 Kelch domain== | |||
<StructureSection load='4in4' size='340' side='right' caption='[[4in4]], [[Resolution|resolution]] 2.59Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4in4]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Streptomyces_aureorectus Streptomyces aureorectus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IN4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IN4 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4ID:2-({5-[(2,4-DIMETHYLPHENYL)SULFONYL]-6-OXO-1,6-DIHYDROPYRIMIDIN-2-YL}SULFANYL)-N-[2-(TRIFLUOROMETHYL)PHENYL]ACETAMIDE'>4ID</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4iqk|4iqk]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">INRF2, KEAP1, KIAA0132, KLHL19 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=285571 Streptomyces aureorectus])</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=4in4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4in4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4in4 RCSB], [http://www.ebi.ac.uk/pdbsum/4in4 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification. | |||
Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism.,Marcotte D, Zeng W, Hus JC, McKenzie A, Hession C, Jin P, Bergeron C, Lugovskoy A, Enyedy I, Cuervo H, Wang D, Atmanene C, Roecklin D, Vecchi M, Vivat V, Kraemer J, Winkler D, Hong V, Chao J, Lukashev M, Silvian L Bioorg Med Chem. 2013 Jul 15;21(14):4011-9. doi: 10.1016/j.bmc.2013.04.019. Epub , 2013 Apr 19. PMID:23647822<ref>PMID:23647822</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
==See Also== | |||
*[[Kelch-like ECH-associated protein 1|Kelch-like ECH-associated protein 1]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Streptomyces aureorectus]] | [[Category: Streptomyces aureorectus]] | ||
[[Category: Marcotte, D | [[Category: Marcotte, D]] | ||
[[Category: Silvian, L | [[Category: Silvian, L]] | ||
[[Category: Transcription]] | [[Category: Transcription]] | ||
Revision as of 12:15, 15 February 2015
Crystal structure of cpd 15 bound to Keap1 Kelch domainCrystal structure of cpd 15 bound to Keap1 Kelch domain
Structural highlights
Publication Abstract from PubMedKeap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification. Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism.,Marcotte D, Zeng W, Hus JC, McKenzie A, Hession C, Jin P, Bergeron C, Lugovskoy A, Enyedy I, Cuervo H, Wang D, Atmanene C, Roecklin D, Vecchi M, Vivat V, Kraemer J, Winkler D, Hong V, Chao J, Lukashev M, Silvian L Bioorg Med Chem. 2013 Jul 15;21(14):4011-9. doi: 10.1016/j.bmc.2013.04.019. Epub , 2013 Apr 19. PMID:23647822[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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