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4zy3

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Revision as of 07:46, 18 May 2023

Crystal Structure of Keap1 in Complex with a small chemical compound, K67

Structural highlights

4zy3 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.

p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming.,Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee MS, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T, Motohashi H, Waguri S, Soga T, Yamamoto M, Tanaka K, Komatsu M Nat Commun. 2016 Jun 27;7:12030. doi: 10.1038/ncomms12030. PMID:27345495^[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
↑ Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee MS, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T, Motohashi H, Waguri S, Soga T, Yamamoto M, Tanaka K, Komatsu M. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun. 2016 Jun 27;7:12030. doi: 10.1038/ncomms12030. PMID:27345495 doi:http://dx.doi.org/10.1038/ncomms12030

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4zy3"

@@ Line 3: / Line 3: @@
 <StructureSection load='4zy3' size='340' side='right'caption='[[4zy3]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4zy3]] is a 2 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=4ZY3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZY3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4zy3]] 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=4ZY3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZY3 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=K67:N,N-[2-(2-OXOPROPYL)NAPHTHALENE-1,4-DIYL]BIS(4-ETHOXYBENZENESULFONAMIDE)'>K67</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=K67:N,N-[2-(2-OXOPROPYL)NAPHTHALENE-1,4-DIYL]BIS(4-ETHOXYBENZENESULFONAMIDE)'>K67</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Keap1, Inrf2, Kiaa0132 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=4zy3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zy3 OCA], [https://pdbe.org/4zy3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zy3 RCSB], [https://www.ebi.ac.uk/pdbsum/4zy3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zy3 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=4zy3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zy3 OCA], [http://pdbe.org/4zy3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zy3 RCSB], [http://www.ebi.ac.uk/pdbsum/4zy3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zy3 ProSAT]</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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 26: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Lk3 transgenic mice]]
+[[Category: Mus musculus]]
-[[Category: Fukutomi, T]]
+[[Category: Fukutomi T]]
-[[Category: Iso, T]]
+[[Category: Iso T]]
-[[Category: Komatsu, M]]
+[[Category: Komatsu M]]
-[[Category: Mizushima, T]]
+[[Category: Mizushima T]]
-[[Category: Suzuki, T]]
+[[Category: Suzuki T]]
-[[Category: Takagi, K]]
+[[Category: Takagi K]]
-[[Category: Yamamoto, M]]
+[[Category: Yamamoto M]]
-[[Category: Double glycine repeat]]
-[[Category: Keap1]]
-[[Category: Kelch domain]]
-[[Category: Nrf2]]
-[[Category: P62]]
-[[Category: Small molecule binding]]
-[[Category: Stress sensor]]
-[[Category: Transcription]]

4zy3

From Proteopedia

Revision as of 07:46, 18 May 2023

Crystal Structure of Keap1 in Complex with a small chemical compound, K67

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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