5daf: Difference between revisions
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==Crystal Structure of Human KEAP1 BTB Domain in Complex with Small Molecule TX64063== | ==Crystal Structure of Human KEAP1 BTB Domain in Complex with Small Molecule TX64063== | ||
<StructureSection load='5daf' size='340' side='right' caption='[[5daf]], [[Resolution|resolution]] 2.37Å' scene=''> | <StructureSection load='5daf' size='340' side='right'caption='[[5daf]], [[Resolution|resolution]] 2.37Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5daf]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5daf]] 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=5DAF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DAF FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=58E:(5AS,6S,9AS)-7-HYDROXY-2,6,9A-TRIMETHYL-3-(PYRIDIN-3-YL)-4,5,5A,6,9,9A-HEXAHYDRO-2H-BENZO[G]INDAZOLE-8-CARBONITRILE'>58E</scene> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=58E:(5AS,6S,9AS)-7-HYDROXY-2,6,9A-TRIMETHYL-3-(PYRIDIN-3-YL)-4,5,5A,6,9,9A-HEXAHYDRO-2H-BENZO[G]INDAZOLE-8-CARBONITRILE'>58E</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=5daf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5daf OCA], [https://pdbe.org/5daf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5daf RCSB], [https://www.ebi.ac.uk/pdbsum/5daf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5daf ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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 == | ||
| Line 18: | Line 18: | ||
</div> | </div> | ||
<div class="pdbe-citations 5daf" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5daf" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Kelch-like protein 3D structures|Kelch-like protein 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Bender | [[Category: Large Structures]] | ||
[[Category: Dulubova | [[Category: Bender CF]] | ||
[[Category: Ferguson | [[Category: Dulubova I]] | ||
[[Category: Huerta | [[Category: Ferguson DA]] | ||
[[Category: Jiang | [[Category: Huerta C]] | ||
[[Category: Probst | [[Category: Jiang X]] | ||
[[Category: Stoll | [[Category: Probst B]] | ||
[[Category: Swinger | [[Category: Stoll VS]] | ||
[[Category: Thomas | [[Category: Swinger KK]] | ||
[[Category: Trevino | [[Category: Thomas PJ]] | ||
[[Category: Visnick | [[Category: Trevino I]] | ||
[[Category: Wigley | [[Category: Visnick M]] | ||
[[Category: Wigley WC]] | |||
Revision as of 13:28, 21 June 2023
Crystal Structure of Human KEAP1 BTB Domain in Complex with Small Molecule TX64063Crystal Structure of Human KEAP1 BTB Domain in Complex with Small Molecule TX64063
Structural highlights
FunctionPublication Abstract from PubMedBACKGROUND: Semi-synthetic oleanane triterpenoid antioxidant inflammation modulators (tpAIMs) are small molecules that interact with KEAP1 cysteine residue 151 (C151) and activate NRF2. Exploration of the structure-activity relationship between the tpAIMs and KEAP1 is limited by the predominantly hydrocarbon nature of the oleanane triterpenoid pentacyclic ring structure. Therefore, we used novel, chemically tractable, synthetic antioxidant inflammation modulators (sAIMs) to probe the stereoselectivity of the ligand-protein interaction. METHODS: We measured several parameters of NRF2 activation to assess the potency of sAIM enantiomers with natural (tpAIM-like) 4(S),5(S),10(R) or unnatural 4(R),5(R),10(S) configurations. Additionally, we determined the crystal structure of the KEAP1 BTB domain in complex with two different sAIMs. RESULTS: We found that the potencies of sAIM enantiomers in the natural configuration were similar to those of the tpAIM, RTA 405. Strikingly, sAIM enantiomers in the unnatural configuration were 10- to 40-fold less potent than their natural counterparts. Crystallographic studies of sAIMs in complex with the KEAP1 BTB domain demonstrated that these ligands form a covalent bond with C151 and revealed the presence of additional hydrogen bonds, Van der Waals interactions, and pi-stacking interactions. CONCLUSIONS: Although KEAP1 C151 is required for NRF2 activation by tpAIMs and sAIMs, interactions with other KEAP1 residues are critical for the stereospecific recognition and potency of these ligands. GENERAL SIGNIFICANCE: This work demonstrates that reversible cyanoenone Michael acceptors, such as the tpAIMs and sAIMs, can be specifically tuned to regulate redox sensitive cysteine residues on key signaling molecules, an approach with significant promise for innovative drug development. Characterization of novel small-molecule NRF2 activators: Structural and biochemical validation of stereospecific KEAP1 binding.,Huerta C, Jiang X, Trevino I, Bender CF, Ferguson DA, Probst B, Swinger KK, Stoll VS, Thomas PJ, Dulubova I, Visnick M, Wigley WC Biochim Biophys Acta. 2016 Jul 27. pii: S0304-4165(16)30273-2. doi:, 10.1016/j.bbagen.2016.07.026. PMID:27474998[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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