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| | ==Crystal structure of cpd 16 bound to Keap1 Kelch domain== | | ==Crystal structure of cpd 16 bound to Keap1 Kelch domain== |
| - | <StructureSection load='4iqk' size='340' side='right' caption='[[4iqk]], [[Resolution|resolution]] 1.97Å' scene=''> | + | <StructureSection load='4iqk' size='340' side='right'caption='[[4iqk]], [[Resolution|resolution]] 1.97Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4iqk]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IQK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IQK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4iqk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4IQK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IQK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IQK:N,N-NAPHTHALENE-1,4-DIYLBIS(4-METHOXYBENZENESULFONAMIDE)'>IQK</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.97Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4in4|4in4]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IQK:N,N-NAPHTHALENE-1,4-DIYLBIS(4-METHOXYBENZENESULFONAMIDE)'>IQK</scene></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=9606 HUMAN])</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=4iqk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4iqk OCA], [https://pdbe.org/4iqk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4iqk RCSB], [https://www.ebi.ac.uk/pdbsum/4iqk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4iqk 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=4iqk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4iqk OCA], [http://pdbe.org/4iqk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4iqk RCSB], [http://www.ebi.ac.uk/pdbsum/4iqk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4iqk ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/KEAP1_HUMAN KEAP1_HUMAN] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Kelch-like protein|Kelch-like protein]] | + | *[[Kelch-like protein 3D structures|Kelch-like protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Marcotte, D]] | + | [[Category: Large Structures]] |
| - | [[Category: Silvian, L]] | + | [[Category: Marcotte D]] |
| - | [[Category: Transcription]] | + | [[Category: Silvian L]] |
| Structural highlights
Function
KEAP1_HUMAN
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg Med Chem. 2013 Jul 15;21(14):4011-9. doi: 10.1016/j.bmc.2013.04.019. Epub , 2013 Apr 19. PMID:23647822 doi:10.1016/j.bmc.2013.04.019
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