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==Crystal structure of human PLU-1 (JARID1B) in complex with KDM5-C49 (2-(((2-((2-(dimethylamino)ethyl)(ethyl)amino)-2-oxoethyl)amino)methyl) isonicotinic acid).== | |||
<StructureSection load='5a3t' size='340' side='right'caption='[[5a3t]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5a3t]] 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=5A3T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5A3T 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]] 1.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=MMK:2-{[(2-{[(E)-2-(DIMETHYLAMINO)ETHENYL](ETHYL)AMINO}-2-OXOETHYL)AMINO]METHYL}PYRIDINE-4-CARBOXYLIC+ACID'>MMK</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</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=5a3t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a3t OCA], [https://pdbe.org/5a3t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5a3t RCSB], [https://www.ebi.ac.uk/pdbsum/5a3t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5a3t ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe2+-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design. | |||
Structural analysis of human KDM5B guides histone demethylase inhibitor development.,Johansson C, Velupillai S, Tumber A, Szykowska A, Hookway ES, Nowak RP, Strain-Damerell C, Gileadi C, Philpott M, Burgess-Brown N, Wu N, Kopec J, Nuzzi A, Steuber H, Egner U, Badock V, Munro S, LaThangue NB, Westaway S, Brown J, Athanasou N, Prinjha R, Brennan PE, Oppermann U Nat Chem Biol. 2016 May 23. doi: 10.1038/nchembio.2087. PMID:27214403<ref>PMID:27214403</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5a3t" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Jumonji domain-containing protein 3D structures|Jumonji domain-containing protein 3D structures]] | ||
[[Category: Gileadi | *[[Lysine-specific histone demethylase 3D structures|Lysine-specific histone demethylase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: Kopec | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Strain-Damerell | [[Category: Large Structures]] | ||
[[Category: | [[Category: Arrowsmith CH]] | ||
[[Category: Bountra C]] | |||
[[Category: BurgessBrown NA]] | |||
[[Category: Edwards AM]] | |||
[[Category: Gileadi C]] | |||
[[Category: Johansson C]] | |||
[[Category: Kopec J]] | |||
[[Category: Kupinska K]] | |||
[[Category: Oppermann U]] | |||
[[Category: Srikannathasan V]] | |||
[[Category: Strain-Damerell C]] | |||
[[Category: Von Delft F]] | |||
Latest revision as of 06:49, 21 November 2024
Crystal structure of human PLU-1 (JARID1B) in complex with KDM5-C49 (2-(((2-((2-(dimethylamino)ethyl)(ethyl)amino)-2-oxoethyl)amino)methyl) isonicotinic acid).Crystal structure of human PLU-1 (JARID1B) in complex with KDM5-C49 (2-(((2-((2-(dimethylamino)ethyl)(ethyl)amino)-2-oxoethyl)amino)methyl) isonicotinic acid).
Structural highlights
Publication Abstract from PubMedMembers of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe2+-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design. Structural analysis of human KDM5B guides histone demethylase inhibitor development.,Johansson C, Velupillai S, Tumber A, Szykowska A, Hookway ES, Nowak RP, Strain-Damerell C, Gileadi C, Philpott M, Burgess-Brown N, Wu N, Kopec J, Nuzzi A, Steuber H, Egner U, Badock V, Munro S, LaThangue NB, Westaway S, Brown J, Athanasou N, Prinjha R, Brennan PE, Oppermann U Nat Chem Biol. 2016 May 23. doi: 10.1038/nchembio.2087. PMID:27214403[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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