5a7o
From Proteopedia
(Difference between revisions)
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| - | ''' | + | ==Crystal structure of human JMJD2A in complex with compound 42== |
| + | <StructureSection load='5a7o' size='340' side='right' caption='[[5a7o]], [[Resolution|resolution]] 2.15Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5a7o]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5A7O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5A7O FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7WH:2-[5-(2-METHOXYETHANOYLAMINO)-2-OXIDANYL-PHENYL]PYRIDINE-4-CARBOXYLIC+ACID'>7WH</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5a7n|5a7n]], [[5a7p|5a7p]], [[5a7q|5a7q]], [[5a7s|5a7s]]</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=5a7o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a7o OCA], [http://pdbe.org/5a7o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5a7o RCSB], [http://www.ebi.ac.uk/pdbsum/5a7o 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 == | ||
| + | Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by approximately 3 log-orders to yield compound 35 (Ki = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors. | ||
| - | + | Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors.,Korczynska M, Le DD, Younger N, Gregori-Puigjane E, Tumber A, Krojer T, Velupillai S, Gileadi C, Nowak RP, Iwasa E, Pollock SB, Ortiz Torres I, Oppermann U, Shoichet BK, Fujimori DG J Med Chem. 2015 Dec 23. PMID:26699912<ref>PMID:26699912</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 5a7o" style="background-color:#fffaf0;"></div> | |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Arrowsmith, C H]] | ||
| + | [[Category: Bountra, C]] | ||
| + | [[Category: Delft, F Von]] | ||
| + | [[Category: Edwards, A]] | ||
| + | [[Category: Fujimori, D G]] | ||
| + | [[Category: Gileadi, C]] | ||
| + | [[Category: Gregori-Puigjane, E]] | ||
| + | [[Category: Iwasa, E]] | ||
| + | [[Category: Johansson, C]] | ||
| + | [[Category: Korczynska, M]] | ||
| + | [[Category: Krojer, T]] | ||
| + | [[Category: Le, D D]] | ||
[[Category: Nowak, R]] | [[Category: Nowak, R]] | ||
| - | [[Category: Ortiz Torres, I]] | ||
| - | [[Category: Pollock, S.B]] | ||
| - | [[Category: Fujimori, D.G]] | ||
| - | [[Category: Arrowsmith, C.H]] | ||
| - | [[Category: Le, D.D]] | ||
| - | [[Category: Gileadi, C]] | ||
[[Category: Oppermann, U]] | [[Category: Oppermann, U]] | ||
| - | [[Category: | + | [[Category: Pinkas, D M]] |
| + | [[Category: Pollock, S B]] | ||
| + | [[Category: Shoichet, B K]] | ||
| + | [[Category: Torres, I Ortiz]] | ||
| + | [[Category: Tumber, A]] | ||
[[Category: Velupillai, S]] | [[Category: Velupillai, S]] | ||
| - | [[Category: Von Delft, F]] | ||
| - | [[Category: Shoichet, B.K]] | ||
[[Category: Younger, N]] | [[Category: Younger, N]] | ||
| - | [[Category: | + | [[Category: Jmjd2a]] |
| - | [[Category: | + | [[Category: Kdm4a]] |
| - | [[Category: | + | [[Category: Oxidoreductase]] |
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Revision as of 20:15, 13 January 2016
Crystal structure of human JMJD2A in complex with compound 42
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Categories: Arrowsmith, C H | Bountra, C | Delft, F Von | Edwards, A | Fujimori, D G | Gileadi, C | Gregori-Puigjane, E | Iwasa, E | Johansson, C | Korczynska, M | Krojer, T | Le, D D | Nowak, R | Oppermann, U | Pinkas, D M | Pollock, S B | Shoichet, B K | Torres, I Ortiz | Tumber, A | Velupillai, S | Younger, N | Jmjd2a | Kdm4a | Oxidoreductase
