3abu

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'''Unreleased structure'''
 
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The entry 3abu is ON HOLD until Paper Publication
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==Crystal Structure of LSD1 in complex with a 2-PCPA derivative, S1201==
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<StructureSection load='3abu' size='340' side='right'caption='[[3abu]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3abu]] 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=3ABU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ABU FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.1&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=12F:[(2R,3S,4R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL+(2R,3S,4S)-5-[(1R,3R,3AS)-3-[2-(BENZYLOXY)-3-FLUOROPHENYL]-1-HYDROXY-10,11-DIMETHYL-4,6-DIOXO-2,3,5,6-TETRAHYDRO-1H-BENZO[G]PYRROLO[2,1-E]PTERIDIN-8(4H)-YL]-2,3,4-TRIHYDROXYPENTYL+DIHYDROGEN+DIPHOSPHATE'>12F</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3abu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3abu OCA], [https://pdbe.org/3abu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3abu RCSB], [https://www.ebi.ac.uk/pdbsum/3abu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3abu ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ab/3abu_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3abu ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Lysine-specific demethylase 1 (LSD1/KDM1) demethylates histone H3, in addition to the tumor suppressor p53 and DNA methyltransferase 1 (Dnmt1), thus regulating eukaryotic gene expression by altering chromatin structure. Specific inhibitors of LSD1 are desired as anti-cancer agents, since LSD1 aberrations are associated with several cancers, and LSD1 inhibition restores the expression of abnormally silenced genes in cancerous cells. In this study, we designed and synthesized several candidate compounds to inhibit LSD1, based on the structures of LSD1 and monoamine oxidase B (MAO-B), in complex with an anti-depressant tranylcypromine (2-PCPA) derivative. The compound S2101 showed stronger LSD1 inhibition than tranylcypromine and the known small LSD1 inhibitors in LSD1 demethylation assays, with &lt;i&gt;k&lt;/i&gt;&lt;sub&gt;inact&lt;/sub&gt;/&lt;i&gt;K&lt;sub&gt;I&lt;/sub&gt;&lt;/i&gt; values of 4560 M &lt;sup&gt;-1&lt;/sup&gt; s &lt;sup&gt;-1&lt;/sup&gt;. In comparison with tranylcypromine, the compound displayed weaker inhibition of the monoamine oxidases. The inhibition modes of the two 2-PCPA derivatives, 2-PFPA and S1201, were identified by determining the inhibitor-bound LSD1 structures, which revealed the enhanced stability of the inhibitor-FAD adducts by their interactions with the surrounding LSD1 residues. These molecules are potential pharmaceutical candidates for cancer or latent virus infection, as well as research tools for LSD1-related biological investigations.&lt;i&gt;&lt;/i&gt;&lt;sub&gt;&lt;/sub&gt;&lt;sup&gt;&lt;/sup&gt;
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Authors: Mimasu, S., Umezawa, N., Sato, S., Higuchi, T., Umehara, T., Yokoyama, S., RIKEN Structural Genomics/Proteomics Initiative (RSGI)
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Structurally Designed &lt;i&gt;Trans&lt;/i&gt;-2-phenylcyclopropylamine Derivatives Potently Inhibit Histone Demethylase LSD1/KDM1.,Mimasu S, Umezawa N, Sato S, Higuchi T, Umehara T, Yokoyama S Biochemistry. 2010 Jun 22. PMID:20568732<ref>PMID:20568732</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3abu" style="background-color:#fffaf0;"></div>
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 3 09:13:50 2010''
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==See Also==
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*[[Lysine-specific histone demethylase 3D structures|Lysine-specific histone demethylase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Higuchi T]]
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[[Category: Mimasu S]]
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[[Category: Sato S]]
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[[Category: Umehara T]]
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[[Category: Umezawa N]]
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[[Category: Yokoyama S]]

Current revision

Crystal Structure of LSD1 in complex with a 2-PCPA derivative, S1201

PDB ID 3abu

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