5anq: Difference between revisions
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==inhibitors of JumonjiC domain-containing histone demethylases== | |||
<StructureSection load='5anq' size='340' side='right' caption='[[5anq]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5anq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ANQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ANQ FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5YQ:2-{2-[(PYRIDIN-3-YLMETHYL)AMINO]PYRIMIDIN-4-YL}PYRIDINE-4-CARBOXYLIC+ACID'>5YQ</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Histone_H3]-lysine-36_demethylase [Histone H3]-lysine-36 demethylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.11.27 1.14.11.27] </span></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=5anq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5anq OCA], [http://pdbe.org/5anq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5anq RCSB], [http://www.ebi.ac.uk/pdbsum/5anq 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 == | |||
BACKGROUND: Aberrant expression of iron(II)- and 2-oxoglutarate-dependent JumonjiC histone demethylases has been linked to cancer. Potent demethylase inhibitors are drug candidates and biochemical tools to elucidate the functional impact of demethylase inhibition. METHODS & RESULTS: Virtual screening identified a novel lead scaffold against JMJD2A with low-micromolar potency in vitro. Analogs were acquired from commercial sources respectively synthesized in feedback with biological testing. Optimized compounds were transformed into cell-permeable prodrugs. A cocrystal x-ray structure revealed the mode of binding of these compounds as competitive to 2-oxoglutarate and confirmed kinetic experiments. Selectivity studies revealed a preference for JMJD2A and JARID1A over JMJD3. CONCLUSION: Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors. | |||
Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases.,Roatsch M, Robaa D, Pippel M, Nettleship JE, Reddivari Y, Bird LE, Hoffmann I, Franz H, Owens RJ, Schule R, Flaig R, Sippl W, Jung M Future Med Chem. 2016 Mar 14. PMID:26971619<ref>PMID:26971619</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[ | </div> | ||
<div class="pdbe-citations 5anq" style="background-color:#fffaf0;"></div> | |||
[[Category: | |||
[[Category: | ==See Also== | ||
*[[Jumonji domain-containing protein|Jumonji domain-containing protein]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bird, L E]] | |||
[[Category: Flaig, R]] | |||
[[Category: Franz, H]] | [[Category: Franz, H]] | ||
[[Category: | [[Category: Hoffmann, I]] | ||
[[Category: Jung, M]] | [[Category: Jung, M]] | ||
[[Category: Nettleship, J | [[Category: Nettleship, J E]] | ||
[[Category: | [[Category: Owens, R J]] | ||
[[Category: Pippel, M]] | [[Category: Pippel, M]] | ||
[[Category: Reddivari, Y]] | [[Category: Reddivari, Y]] | ||
[[Category: Roatsch, M]] | |||
[[Category: Robaa, D]] | |||
[[Category: Schuele, R]] | |||
[[Category: Sippl, W]] | |||
[[Category: Epigenetic]] | |||
[[Category: Histone demethylase]] | |||
[[Category: Inhibitor]] | |||
[[Category: Jumonjic domain]] | |||
[[Category: Oxidoreductase]] | |||
[[Category: Virtual screening]] | |||
Revision as of 12:59, 11 May 2016
inhibitors of JumonjiC domain-containing histone demethylases
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