5anq
From Proteopedia
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| - | '''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 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=5ANQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ANQ 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]] 2Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5anq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5anq OCA], [https://pdbe.org/5anq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5anq RCSB], [https://www.ebi.ac.uk/pdbsum/5anq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5anq ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://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> |
| - | [[Category: | + | <div class="pdbe-citations 5anq" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | |
| - | [[Category: | + | ==See Also== |
| - | [[Category: | + | *[[Jumonji domain-containing protein 3D structures|Jumonji domain-containing protein 3D structures]] |
| - | [[Category: Franz | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: Jung | + | __TOC__ |
| - | [[Category: Nettleship | + | </StructureSection> |
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: Pippel | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Bird LE]] |
| - | [[Category: | + | [[Category: Flaig R]] |
| - | [[Category: | + | [[Category: Franz H]] |
| + | [[Category: Hoffmann I]] | ||
| + | [[Category: Jung M]] | ||
| + | [[Category: Nettleship JE]] | ||
| + | [[Category: Owens RJ]] | ||
| + | [[Category: Pippel M]] | ||
| + | [[Category: Reddivari Y]] | ||
| + | [[Category: Roatsch M]] | ||
| + | [[Category: Robaa D]] | ||
| + | [[Category: Schuele R]] | ||
| + | [[Category: Sippl W]] | ||
Current revision
inhibitors of JumonjiC domain-containing histone demethylases
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Categories: Homo sapiens | Large Structures | Bird LE | Flaig R | Franz H | Hoffmann I | Jung M | Nettleship JE | Owens RJ | Pippel M | Reddivari Y | Roatsch M | Robaa D | Schuele R | Sippl W
