5h6r
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of LSD1-CoREST in complex with peptide 13== | |
| + | <StructureSection load='5h6r' size='340' side='right'caption='[[5h6r]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5h6r]] is a 3 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=5H6R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5H6R FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HSE:L-HOMOSERINE'>HSE</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=5h6r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5h6r OCA], [https://pdbe.org/5h6r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5h6r RCSB], [https://www.ebi.ac.uk/pdbsum/5h6r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5h6r ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [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 == | ||
| + | Lysine-specific demethylase 1 (LSD1/KDM1A) is a flavoenzyme demethylase, which removes mono- and dimethyl groups from histone H3 Lys4 (H3K4) or Lys9 (H3K9) in complexes with several nuclear proteins. Since LSD1 is implicated in the tumorigenesis and progression of various cancers, LSD1-specific inhibitors are considered as potential anti-cancer agents. A modified H3 peptide with substitution of Lys4 to Met [H3K4M] is already known to be a potent competitive inhibitor of LSD1. In this study, we synthesized a series of H3K4M peptide derivatives and evaluated their LSD1-inhibitory activities in vitro. We found that substitutions of the N-terminal amino acid with amino acids having a larger side chain were generally not tolerated, but substitution of Ala1 to Ser unexpectedly resulted in more potent inhibitory activity toward LSD1. X-ray crystallographic analysis of H3K4M derivatives bound to the LSD1.CoREST complex revealed the presence of additional hydrogen bonding between the N-terminal Ser residue of the H3 peptide derivative and LSD1. The present structural and biochemical findings will be helpful for obtaining more potent peptidic inhibitors of LSD1. | ||
| - | + | Development and crystallographic evaluation of histone H3 peptide with N-terminal serine substitution as a potent inhibitor of lysine-specific demethylase 1.,Amano Y, Kikuchi M, Sato S, Yokoyama S, Umehara T, Umezawa N, Higuchi T Bioorg Med Chem. 2017 May 1;25(9):2617-2624. doi: 10.1016/j.bmc.2017.03.016. Epub, 2017 Mar 9. PMID:28336409<ref>PMID:28336409</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Amano | + | <div class="pdbe-citations 5h6r" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | |
| - | [[Category: Kkuchi | + | ==See Also== |
| - | [[Category: | + | *[[Lysine-specific histone demethylase 3D structures|Lysine-specific histone demethylase 3D structures]] |
| - | [[Category: | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: Yokoyama | + | __TOC__ |
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Amano Y]] | ||
| + | [[Category: Higuchi T]] | ||
| + | [[Category: Kkuchi M]] | ||
| + | [[Category: Sato S]] | ||
| + | [[Category: Umehara T]] | ||
| + | [[Category: Umezawa N]] | ||
| + | [[Category: Yokoyama S]] | ||
Current revision
Crystal structure of LSD1-CoREST in complex with peptide 13
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Categories: Homo sapiens | Large Structures | Amano Y | Higuchi T | Kkuchi M | Sato S | Umehara T | Umezawa N | Yokoyama S
