View source for 5f37


==Crystal structure of human KDM4A in complex with compound 58==
<StructureSection load='5f37' size='340' side='right' caption='[[5f37]], [[Resolution|resolution]] 2.22&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5f37]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F37 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5F37 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=N5J:3H-PYRIDO[3,4-D]PYRIMIDIN-4-ONE'>N5J</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5f37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f37 OCA], [http://pdbe.org/5f37 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5f37 RCSB], [http://www.ebi.ac.uk/pdbsum/5f37 PDBsum]</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 ==
We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.

8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.,Bavetsias V, Lanigan RM, Ruda GF, Atrash B, McLaughlin MG, Tumber A, Mok NY, Le Bihan YV, Dempster S, Boxall KJ, Jeganathan F, Hatch SB, Savitsky P, Velupillai S, Krojer T, England KS, Sejberg J, Thai C, Donovan A, Pal A, Scozzafava G, Bennett JM, Kawamura A, Johansson C, Szykowska A, Gileadi C, Burgess-Brown NA, von Delft F, Oppermann U, Walters Z, Shipley J, Raynaud FI, Westaway SM, Prinjha RK, Fedorov O, Burke R, Schofield CJ, Westwood IM, Bountra C, Muller S, van Montfort RL, Brennan PE, Blagg J J Med Chem. 2016 Jan 7. PMID:26741168<ref>PMID:26741168</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5f37" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bihan, Y V.Le]]
[[Category: Dempster, S]]
[[Category: Montfort, R L.M van]]
[[Category: Westwood, I M]]
[[Category: Demethylase]]
[[Category: Epigenetic]]
[[Category: Inhibitor]]
[[Category: Oxidoreductase]]