This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
5anq
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==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: Sippl, W]] | ||
| - | [[Category: Jung, M]] | ||
| - | [[Category: Nettleship, J.E]] | ||
[[Category: Hoffmann, I]] | [[Category: Hoffmann, I]] | ||
| + | [[Category: Jung, M]] | ||
| + | [[Category: Nettleship, J E]] | ||
| + | [[Category: Owens, R J]] | ||
[[Category: Pippel, M]] | [[Category: Pippel, M]] | ||
| - | [[Category: Flaig, R]] | ||
| - | [[Category: Bird, L.E]] | ||
[[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
| |||||||||||
Categories: Bird, L E | Flaig, R | Franz, H | Hoffmann, I | Jung, M | Nettleship, J E | Owens, R J | Pippel, M | Reddivari, Y | Roatsch, M | Robaa, D | Schuele, R | Sippl, W | Epigenetic | Histone demethylase | Inhibitor | Jumonjic domain | Oxidoreductase | Virtual screening
