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[[Image:2z3y.jpg|left|200px]]<br /><applet load="2z3y" size="350" color="white" frame="true" align="right" spinBox="true"
caption="2z3y, resolution 2.25&Aring;" />
'''Crystal structure of Lysine-specific demethylase1'''<br />


==Overview==
==Crystal structure of Lysine-specific demethylase1==
Transcriptional activity and chromatin structure accessibility are correlated with the methylation of specific histone residues. Lysine-specific demethylase 1 (LSD1) is the first discovered histone demethylase, which demethylates Lys4 or Lys9 of histone H3, using FAD. Among the known monoamine oxidase inhibitors, tranylcypromine (Parnate) showed the most potent inhibitory effect on LSD1. Recently, the crystal structure of LSD1 and tranylcypromine was solved at 2.75 A, revealing a five-membered ring fused to the flavin of LSD1. In this study, we refined the crystal structure of the LSD1-tranylcypromine complex to 2.25 A. The five-membered ring model did not fit completely with the electron density, giving R(work)/R(free) values of 0.226/0.254. On the other hand, the N(5) adduct gave the lowest R(work)/R(free) values of 0.218/0.248, among the tested models. These results imply that the LSD1-tranylcypromine complex is not completely composed of the five-membered adduct, but partially contains an intermediate, such as the N(5) adduct.
<StructureSection load='2z3y' size='340' side='right'caption='[[2z3y]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2z3y]] 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=2Z3Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Z3Y 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]] 2.25&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F2N:[(2R,3S,4R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL+(2R,3S,4S)-5-[7,8-DIMETHYL-2,4-DIOXO-5-(3-PHENYLPROPANOYL)-1,3,4,5-TETRAHYDROBENZO[G]PTERIDIN-10(2H)-YL]-2,3,4-TRIHYDROXYPENTYL+DIHYDROGEN+DIPHOSPHATE'>F2N</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=2z3y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2z3y OCA], [https://pdbe.org/2z3y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2z3y RCSB], [https://www.ebi.ac.uk/pdbsum/2z3y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2z3y 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/z3/2z3y_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=2z3y ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
2Z3Y 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 <scene name='pdbligand=F2N:'>F2N</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Z3Y OCA].
*[[Lysine-specific histone demethylase 3D structures|Lysine-specific histone demethylase 3D structures]]
 
== References ==
==Reference==
<references/>
Crystal structure of histone demethylase LSD1 and tranylcypromine at 2.25 A., Mimasu S, Sengoku T, Fukuzawa S, Umehara T, Yokoyama S, Biochem Biophys Res Commun. 2008 Feb 1;366(1):15-22. Epub 2007 Nov 26. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18039463 18039463]
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Mimasu, S.]]
[[Category: Mimasu S]]
[[Category: RSGI, RIKEN Structural Genomics/Proteomics Initiative.]]
[[Category: Sengoku T]]
[[Category: Sengoku, T.]]
[[Category: Umehara T]]
[[Category: Umehara, T.]]
[[Category: Yokoyama S]]
[[Category: Yokoyama, S.]]
[[Category: F2N]]
[[Category: alternative splicing]]
[[Category: chromatin]]
[[Category: chromatin regulator]]
[[Category: coiled coil]]
[[Category: crystal structure]]
[[Category: fad]]
[[Category: histone demethylase]]
[[Category: lsd1]]
[[Category: lysine-specific]]
[[Category: national project on protein structural and functional analyses]]
[[Category: nppsfa]]
[[Category: nucleosome]]
[[Category: nucleus]]
[[Category: oxidoreductase]]
[[Category: phosphorylation]]
[[Category: repressor]]
[[Category: riken structural genomics/proteomics initiative]]
[[Category: rsgi]]
[[Category: structural genomics]]
[[Category: transcription]]
[[Category: transcription regulation]]
 
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