1x2j

From Proteopedia

(Difference between revisions)

Revision as of 16:33, 27 October 2021

Structural basis for the defects of human lung cancer somatic mutations in the repression activity of Keap1 on Nrf2

Structural highlights

1x2j is a 1 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1x2r
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT, TOPSAN

Function

[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).^[1] ^[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses Nrf2 through its molecular interaction. To elucidate the molecular mechanism of the Keap1 and Nrf2 interaction, we resolved the six-bladed beta propeller crystal structure of the Kelch/DGR and CTR domains of mouse Keap1 and revealed that extensive inter- and intrablade hydrogen bonds maintain the structural integrity and proper association of Keap1 with Nrf2. A peptide containing the ETGE motif of Nrf2 binds the beta propeller of Keap1 at the entrance of the central cavity on the bottom side via electrostatic interactions with conserved arginine residues. We found a somatic mutation and a gene variation in human lung cancer cells that change glycine to cysteine in the DGR domain, introducing local conformational changes that reduce Keap1's affinity for Nrf2. These results provide a structural basis for the loss of Keap1 function and gain of Nrf2 function.

Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer.,Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang MI, Kobayashi A, Yokoyama S, Yamamoto M Mol Cell. 2006 Mar 3;21(5):689-700. PMID:16507366^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999 Jan 1;13(1):76-86. PMID:9887101
↑ McMahon M, Itoh K, Yamamoto M, Hayes JD. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem. 2003 Jun 13;278(24):21592-600. Epub 2003 Apr 7. PMID:12682069 doi:10.1074/jbc.M300931200
↑ Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang MI, Kobayashi A, Yokoyama S, Yamamoto M. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell. 2006 Mar 3;21(5):689-700. PMID:16507366 doi:10.1016/j.molcel.2006.01.013

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1x2j"

@@ Line 3: / Line 3: @@
 <StructureSection load='1x2j' size='340' side='right'caption='[[1x2j]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1x2j]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1X2J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1X2J FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1x2j]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1X2J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1X2J FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1x2r|1x2r]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1x2r|1x2r]]</div></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=1x2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1x2j OCA], [http://pdbe.org/1x2j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1x2j RCSB], [http://www.ebi.ac.uk/pdbsum/1x2j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1x2j ProSAT], [http://www.topsan.org/Proteins/RSGI/1x2j TOPSAN]</span></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=1x2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1x2j OCA], [https://pdbe.org/1x2j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1x2j RCSB], [https://www.ebi.ac.uk/pdbsum/1x2j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1x2j ProSAT], [https://www.topsan.org/Proteins/RSGI/1x2j TOPSAN]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[[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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]

1x2j

From Proteopedia

Revision as of 16:33, 27 October 2021

Structural basis for the defects of human lung cancer somatic mutations in the repression activity of Keap1 on Nrf2

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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