6nr5: Difference between revisions

No edit summary
No edit summary
 
Line 3: Line 3:
<StructureSection load='6nr5' size='340' side='right'caption='[[6nr5]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
<StructureSection load='6nr5' size='340' side='right'caption='[[6nr5]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6nr5]] 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=6NR5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NR5 FirstGlance]. <br>
<table><tr><td colspan='2'>[[6nr5]] 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=6NR5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NR5 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=KXM:[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl+(2R,3R,4R)-5-[(4aR)-7,8-dimethyl-2,4-dioxo-5-(2-phenylethyl)-3,4,4a,5-tetrahydrobenzo[g]pteridin-10(2H)-yl]-2,3,4-trihydroxypentyl+dihydrogen+diphosphate+(non-preferred+name)'>KXM</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]] 2.9&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KDM1A, AOF2, KDM1, KIAA0601, LSD1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KXM:[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl+(2R,3R,4R)-5-[(4aR)-7,8-dimethyl-2,4-dioxo-5-(2-phenylethyl)-3,4,4a,5-tetrahydrobenzo[g]pteridin-10(2H)-yl]-2,3,4-trihydroxypentyl+dihydrogen+diphosphate+(non-preferred+name)'>KXM</scene></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=6nr5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nr5 OCA], [http://pdbe.org/6nr5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nr5 RCSB], [http://www.ebi.ac.uk/pdbsum/6nr5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nr5 ProSAT]</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=6nr5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nr5 OCA], [https://pdbe.org/6nr5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nr5 RCSB], [https://www.ebi.ac.uk/pdbsum/6nr5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nr5 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/KDM1A_HUMAN KDM1A_HUMAN]] Histone demethylase that demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.<ref>PMID:12032298</ref> <ref>PMID:15620353</ref> <ref>PMID:16079795</ref> <ref>PMID:17805299</ref> <ref>PMID:20228790</ref
[https://www.uniprot.org/uniprot/KDM1A_HUMAN KDM1A_HUMAN] Histone demethylase that demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.<ref>PMID:12032298</ref> <ref>PMID:15620353</ref> <ref>PMID:16079795</ref> <ref>PMID:17805299</ref> <ref>PMID:20228790</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Macrophages play an important role in regulating the tumor microenvironment (TME). Here we show that classical (M1) macrophage polarization reduced expression of LSD1, nuclear REST corepressor 1 (CoREST), and the zinc finger protein SNAIL. The LSD1 inhibitor phenelzine targeted both the flavin adenine dinucleotide (FAD) and CoREST binding domains of LSD1, unlike the LSD1 inhibitor GSK2879552, which only targeted the FAD domain. Phenelzine treatment reduced nuclear demethylase activity and increased transcription and expression of M1-like signatures both in vitro and in a murine triple-negative breast cancer model. Overall, the LSD1 inhibitors phenelzine and GSK2879552 are useful tools for dissecting the contribution of LSD1 demethylase activity and the nuclear LSD1-CoREST complex to switching macrophage polarization programs. These findings suggest that inhibitors must have dual FAD and CoREST targeting abilities to successfully initiate or prime macrophages toward an anti-tumor M1-like phenotype in triple-negative breast cancer.
 
Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer.,Tan AHY, Tu W, McCuaig R, Hardy K, Donovan T, Tsimbalyuk S, Forwood JK, Rao S Front Immunol. 2019 Jun 12;10:1351. doi: 10.3389/fimmu.2019.01351. eCollection, 2019. PMID:31249575<ref>PMID:31249575</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6nr5" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
Line 26: Line 17:
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Donovan, T]]
[[Category: Donovan T]]
[[Category: Forwood, J K]]
[[Category: Forwood JK]]
[[Category: McCuaig, R]]
[[Category: McCuaig R]]
[[Category: Rao, S]]
[[Category: Rao S]]
[[Category: Tan, A H.Y]]
[[Category: Tan AHY]]
[[Category: Tsimbalyuk, S]]
[[Category: Tsimbalyuk S]]
[[Category: Tu, W]]
[[Category: Tu W]]
[[Category: Complex]]
[[Category: Inhibitor]]
[[Category: Lysine-specific histone demethylase 1a]]
[[Category: Oxidoreductase]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA