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[[Image:2v1d.gif|left|200px]]<br />
<applet load="2v1d" size="450" color="white" frame="true" align="right" spinBox="true"
caption="2v1d, resolution 3.10&Aring;" />
'''STRUCTURAL BASIS OF LSD1-COREST SELECTIVITY IN HISTONE H3 RECOGNITION'''<br />


==Overview==
==Structural basis of LSD1-CoREST selectivity in histone H3 recognition==
Histone demethylase LSD1 regulates transcription by demethylating Lys(4), of histone H3. The crystal structure of the enzyme in complex with CoREST, and a substrate-like peptide inhibitor highlights an intricate network of, interactions and a folded conformation of the bound peptide. The core of, the peptide structure is formed by Arg(2), Gln(5), and Ser(10), which are, engaged in specific intramolecular H-bonds. Several charged side chains on, the surface of the substrate-binding pocket establish electrostatic, interactions with the peptide. The three-dimensional structure predicts, that methylated Lys(4) binds in a solvent inaccessible position in front, of the flavin cofactor. This geometry is fully consistent with the, demethylation reaction being catalyzed through a flavin-mediated oxidation, of the substrate amino-methyl group. These features dictate the exquisite, substrate specificity of LSD1 and provide a structural framework to, explain the fine tuning of its catalytic activity and the active role of, CoREST in substrate recognition.
<StructureSection load='2v1d' size='340' side='right'caption='[[2v1d]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2v1d]] 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=2V1D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2V1D 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]] 3.1&#8491;</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></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=2v1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v1d OCA], [https://pdbe.org/2v1d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2v1d RCSB], [https://www.ebi.ac.uk/pdbsum/2v1d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2v1d 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>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/v1/2v1d_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=2v1d ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Histone demethylase LSD1 regulates transcription by demethylating Lys(4) of histone H3. The crystal structure of the enzyme in complex with CoREST and a substrate-like peptide inhibitor highlights an intricate network of interactions and a folded conformation of the bound peptide. The core of the peptide structure is formed by Arg(2), Gln(5), and Ser(10), which are engaged in specific intramolecular H-bonds. Several charged side chains on the surface of the substrate-binding pocket establish electrostatic interactions with the peptide. The three-dimensional structure predicts that methylated Lys(4) binds in a solvent inaccessible position in front of the flavin cofactor. This geometry is fully consistent with the demethylation reaction being catalyzed through a flavin-mediated oxidation of the substrate amino-methyl group. These features dictate the exquisite substrate specificity of LSD1 and provide a structural framework to explain the fine tuning of its catalytic activity and the active role of CoREST in substrate recognition.


==About this Structure==
Structural basis of LSD1-CoREST selectivity in histone H3 recognition.,Forneris F, Binda C, Adamo A, Battaglioli E, Mattevi A J Biol Chem. 2007 Jul 13;282(28):20070-4. Epub 2007 May 30. PMID:17537733<ref>PMID:17537733</ref>
2V1D is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FAD as [http://en.wikipedia.org/wiki/ligand ligand]. Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2V1D OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
Structural Basis of LSD1-CoREST Selectivity in Histone H3 Recognition., Forneris F, Binda C, Adamo A, Battaglioli E, Mattevi A, J Biol Chem. 2007 Jul 13;282(28):20070-4. Epub 2007 May 30. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17537733 17537733]
</div>
<div class="pdbe-citations 2v1d" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Lysine-specific histone demethylase|Lysine-specific histone demethylase]]
*[[Lysine-specific histone demethylase 3D structures|Lysine-specific histone demethylase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Large Structures]]
[[Category: Adamo, A.]]
[[Category: Adamo A]]
[[Category: Battaglioli, E.]]
[[Category: Battaglioli E]]
[[Category: Binda, C.]]
[[Category: Binda C]]
[[Category: Forneris, F.]]
[[Category: Forneris F]]
[[Category: Mattevi, A.]]
[[Category: Mattevi A]]
[[Category: FAD]]
[[Category: alternative splicing]]
[[Category: amine oxidase]]
[[Category: chromatin regulator]]
[[Category: coiled coil]]
[[Category: fad]]
[[Category: flavin]]
[[Category: histone demethylase]]
[[Category: host-virus interaction]]
[[Category: lsd1]]
[[Category: nuclear protein]]
[[Category: oxidoreductase]]
[[Category: oxidoreductase/repressor complex chromatin remodelling]]
[[Category: phosphorylation]]
[[Category: repressor]]
[[Category: transcription]]
[[Category: transcription regulation]]
 
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