View source for 5ly1


==JMJD2A/ KDM4A COMPLEXED WITH NI(II) AND Macrocyclic PEPTIDE Inhibitor CP2 (13-mer)==
<StructureSection load='5ly1' size='340' side='right' caption='[[5ly1]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ly1]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LY1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LY1 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=PPI:PROPANOIC+ACID'>PPI</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=48V:{[(2R)-2,3-DIAMINO-3-OXOPROPYL]SULFANYL}ACETIC+ACID'>48V</scene>, <scene name='pdbligand=DTY:D-TYROSINE'>DTY</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2ox0|2ox0]], [[4v2v|4v2v]], [[4bis|4bis]], [[4ai9|4ai9]], [[2ybp|2ybp]], [[5ly2|5ly2]]</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ly1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ly1 OCA], [http://pdbe.org/5ly1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ly1 RCSB], [http://www.ebi.ac.uk/pdbsum/5ly1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ly1 ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/KDM4A_HUMAN KDM4A_HUMAN]] Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively.<ref>PMID:16024779</ref> <ref>PMID:16603238</ref> <ref>PMID:21694756</ref>   Isoform 2: Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain.<ref>PMID:16024779</ref> <ref>PMID:16603238</ref> <ref>PMID:21694756</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-varepsilon-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs.

Highly selective inhibition of histone demethylases by de novo macrocyclic peptides.,Kawamura A, Munzel M, Kojima T, Yapp C, Bhushan B, Goto Y, Tumber A, Katoh T, King ON, Passioura T, Walport LJ, Hatch SB, Madden S, Muller S, Brennan PE, Chowdhury R, Hopkinson RJ, Suga H, Schofield CJ Nat Commun. 2017 Apr 6;8:14773. doi: 10.1038/ncomms14773. PMID:28382930<ref>PMID:28382930</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ly1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Chowdhury, R]]
[[Category: Kawamura, A]]
[[Category: King, O N.F]]
[[Category: Schofield, C J]]
[[Category: 2-oxoglutarate]]
[[Category: Chromatin regulator]]
[[Category: Demethylase]]
[[Category: Dioxygenase]]
[[Category: Double-stranded beta helix]]
[[Category: Dsbh]]
[[Category: Epigenetic and transcription regulation]]
[[Category: Facial triad]]
[[Category: Histone]]
[[Category: Hydroxylation]]
[[Category: Iron]]
[[Category: Jmjc domain]]
[[Category: Jmjd2a]]
[[Category: Kdm4a]]
[[Category: Metal binding protein]]
[[Category: Non-heme]]
[[Category: Oxidoreductase]]
[[Category: Oxygenase]]