5var
From Proteopedia
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==Crystal structure of KDM4A tandem TUDOR domain in complex with a tri-methyl lysine competitive inhibitor== | ==Crystal structure of KDM4A tandem TUDOR domain in complex with a tri-methyl lysine competitive inhibitor== | ||
| - | <StructureSection load='5var' size='340' side='right' caption='[[5var]], [[Resolution|resolution]] 1.83Å' scene=''> | + | <StructureSection load='5var' size='340' side='right'caption='[[5var]], [[Resolution|resolution]] 1.83Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5var]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VAR OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[5var]] is a 1 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=5VAR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VAR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=92Y:(1R,2S,3R,4S)-3-[(dimethylamino)methyl]-1-phenylbicyclo[2.2.1]heptan-2-ol'>92Y</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.83Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=92Y:(1R,2S,3R,4S)-3-[(dimethylamino)methyl]-1-phenylbicyclo[2.2.1]heptan-2-ol'>92Y</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=5var FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5var OCA], [https://pdbe.org/5var PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5var RCSB], [https://www.ebi.ac.uk/pdbsum/5var PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5var ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == 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 == | ||
| + | The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays. A co-crystal structure of KDM4A TUDOR domain in complex with 1a shows that the fragment binds stereo-specifically to the methyl lysine binding pocket forming a network of strong hydrogen bonds and hydrophobic interactions. We anticipate that the fragment 1a can be further developed into a novel allosteric inhibitor of the KDM4 family of enzymes through targeting their C-terminal tandem TUDOR domain. | ||
| + | |||
| + | Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain - A fragment based approach.,Upadhyay AK, Judge RA, Li L, Pithawalla R, Simanis J, Bodelle PM, Marin VL, Henry RF, Petros AM, Sun C Bioorg Med Chem Lett. 2018 Jun 1;28(10):1708-1713. doi:, 10.1016/j.bmcl.2018.04.050. Epub 2018 Apr 19. PMID:29691138<ref>PMID:29691138</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5var" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Jumonji domain-containing protein 3D structures|Jumonji domain-containing protein 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Judge RA]] |
| - | [[Category: | + | [[Category: Upadhyay AK]] |
Current revision
Crystal structure of KDM4A tandem TUDOR domain in complex with a tri-methyl lysine competitive inhibitor
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