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New page: left|200px<br /> <applet load="2h94" size="450" color="white" frame="true" align="right" spinBox="true" caption="2h94, resolution 2.900Å" /> '''Crystal Structure ...
 
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[[Image:2h94.gif|left|200px]]<br />
<applet load="2h94" size="450" color="white" frame="true" align="right" spinBox="true"
caption="2h94, resolution 2.900&Aring;" />
'''Crystal Structure and Mechanism of human Lysine-Specific Demethylase-1'''<br />


==Overview==
==Crystal Structure and Mechanism of human Lysine-Specific Demethylase-1==
The reversible methylation of specific lysine residues in histone tails is, crucial in epigenetic gene regulation. LSD1, the first known, lysine-specific demethylase, selectively removes monomethyl and dimethyl, but not trimethyl modifications of Lys4 or Lys9 of histone-3. Here, we, present the crystal structure of LSD1 at 2.9-A resolution. LSD1 forms a, highly asymmetric, closely packed domain structure from which a long, helical 'tower' domain protrudes. The active site cavity is spacious, enough to accommodate several residues of the histone tail substrate, but, does not appear capable of recognizing the different methylation states of, the substrate lysine. This supports the hypothesis that trimethylated, lysine is chemically rather than sterically discriminated. We present a, biochemical analysis of LSD1 mutants that identifies crucial residues in, the active site cavity and shows the importance of the SWIRM and tower, domains for catalysis.
<StructureSection load='2h94' size='340' side='right'caption='[[2h94]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2h94]] 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=2H94 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2H94 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]] 2.9&#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>, <scene name='pdbligand=HG:MERCURY+(II)+ION'>HG</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=2h94 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h94 OCA], [https://pdbe.org/2h94 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2h94 RCSB], [https://www.ebi.ac.uk/pdbsum/2h94 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2h94 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/h9/2h94_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=2h94 ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
2H94 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with HG and FAD as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2H94 OCA].
*[[Lysine-specific demethylase 1 (LSD-1)|Lysine-specific demethylase 1 (LSD-1)]]
 
*[[Lysine-specific histone demethylase 3D structures|Lysine-specific histone demethylase 3D structures]]
==Reference==
== References ==
Crystal structure and mechanism of human lysine-specific demethylase-1., Stavropoulos P, Blobel G, Hoelz A, Nat Struct Mol Biol. 2006 Jul;13(7):626-32. Epub 2006 Jun 25. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16799558 16799558]
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Blobel, G.]]
[[Category: Blobel G]]
[[Category: Hoelz, A.]]
[[Category: Hoelz A]]
[[Category: Stavropoulos, P.]]
[[Category: Stavropoulos P]]
[[Category: FAD]]
[[Category: HG]]
[[Category: histone demethylase]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:28:34 2007''

Latest revision as of 09:31, 14 February 2024

Crystal Structure and Mechanism of human Lysine-Specific Demethylase-1

2h94, resolution 2.90Å

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