7eca
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | ==== | + | ==Crystal structure of the Keap1 complex with a peptide base on ETGE motif.== |
| - | <StructureSection load='7eca' size='340' side='right'caption='[[7eca]]' scene=''> | + | <StructureSection load='7eca' size='340' side='right'caption='[[7eca]], [[Resolution|resolution]] 2.00Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7eca]] is a 2 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=7ECA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ECA FirstGlance]. <br> |
| - | </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=7eca FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7eca OCA], [https://pdbe.org/7eca PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7eca RCSB], [https://www.ebi.ac.uk/pdbsum/7eca PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7eca ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7eca FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7eca OCA], [https://pdbe.org/7eca PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7eca RCSB], [https://www.ebi.ac.uk/pdbsum/7eca PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7eca ProSAT]</span></td></tr> | ||
</table> | </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 == | ||
| + | AIMS: Keap1-Nrf2 signaling pathway is one of the most important antioxidant signaling pathways, and its abnormal activation is related to cancer metastasis and drug resistance. Many studies have shown Keap1 and Nrf2 mutations are closely associated with cancer occurrence. However, few studies focus on Keap1-Nrf2 binding characteristics of cancer-associated mutations. The study investigated the molecular mechanism between Keap1/Nrf2 mutations and cancer. MAIN METHODS: We have determined the crystal structure of the Keap1-Kelch domain with Nrf2 25-mer peptide. What's more, we clarified the molecular effects of Nrf2(Thr80) and Nrf2(Pro85) on the binding of Keap1 by the method isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF) and electrophoretic mobility shift assay (EMSA). Especially, we confirmed the effect of Thr80 and Pro85 mutations on Keap1/Nrf2 signaling pathway in HEK293T cells by RT-PCR and western blot (WB). Finally, we verified the effect of six cancer-related high-frequency somatic mutations Keap1(G364C), Keap1(D422N), Keap1(R470C), Keap1(G480W), Keap1(E493Q) and Keap1(R601L) on binding with Nrf2 through ITC experiments. KEY FINDINGS: Nrf2(Thr80) and Nrf2(Pro85) play a vital role in the Keap1-Nrf2 interaction. Mutant or modification at position Thr80 will disrupt the interaction. Especially, Nrf2(Thr80) and Nrf2(Pro85) mutations activate the expression of cytoprotective genes in HEK293T cells. As for Keap1, except G364C, the binding affinity of other cancer-related mutants to Nrf2 hardly changed, which means that Keap1 mutants can activate Nrf2 without disrupting the binding to Nrf2. SIGNIFICANCE: The study provides new insight into Keap1/Nrf2 signaling pathway and cancer. | ||
| + | |||
| + | New insights into the mechanism of Keap1-Nrf2 interaction based on cancer-associated mutations.,Cheng L, Wang H, Li S, Liu Z, Wang C Life Sci. 2021 Oct 1;282:119791. doi: 10.1016/j.lfs.2021.119791. Epub 2021 Jul 3. PMID:34229009<ref>PMID:34229009</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7eca" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Mus musculus]] |
| + | [[Category: Cheng L]] | ||
| + | [[Category: Wang C]] | ||
Revision as of 03:46, 8 September 2022
Crystal structure of the Keap1 complex with a peptide base on ETGE motif.
| |||||||||||
