6g5x

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(New page: '''Unreleased structure''' The entry 6g5x is ON HOLD Authors: Description: Category: Unreleased Structures)
Current revision (11:50, 1 February 2024) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 6g5x is ON HOLD
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==Crystal Structure of KDM4A with compound YP-02-145==
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<StructureSection load='6g5x' size='340' side='right'caption='[[6g5x]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6g5x]] 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=6G5X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6G5X FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.78&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MY7:2-(3-methyl-5-oxidanylidene-4-phenyl-4~{H}-pyrazol-1-yl)-3~{H}-benzimidazole-5-carboxylic+acid'>MY7</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6g5x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g5x OCA], [https://pdbe.org/6g5x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6g5x RCSB], [https://www.ebi.ac.uk/pdbsum/6g5x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6g5x ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Jumonji domain-containing lysine demethylase (KDM) enzymes are encoded by genes of the KDM superfamily. Activities of the KDM4 subfamily promote aggressive phenotypes associated with prostate cancer (PCa). Previously, we discovered a benzimidazole pyrazole molecule that inhibited KDM4 isoforms with properties tractable for development. Here, we demonstrate that a benzyl-substituted variant of this inhibitor exhibits improved potency in biochemical assays, is cell-permeable, and kills PCa cells at low micromolar concentrations. By X-ray crystallography and kinetics-based assays, we demonstrate that the mechanism of inhibition is complex, proceeding via competition with the enzyme for binding of active-site Fe(2+) and by populating a distal site on the enzyme surface. Furthermore, we provide evidence that the inhibitor's cytostatic properties arise from direct intracellular inhibition of KDM4 enzymes. PCa cells treated with the inhibitor exhibit reduced expression of genes regulated by the androgen receptor, an outcome accompanied by epigenetic maintenance of a heterochromatic state.
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Authors:
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Enhanced Properties of a Benzimidazole Benzylpyrazole Lysine Demethylase Inhibitor: Mechanism-of-Action, Binding Site Analysis, and Activity in Cellular Models of Prostate Cancer.,Carter DM, Specker E, Malecki PH, Przygodda J, Dudaniec K, Weiss MS, Heinemann U, Nazare M, Gohlke U J Med Chem. 2021 Oct 14;64(19):14266-14282. doi: 10.1021/acs.jmedchem.1c00693. , Epub 2021 Sep 23. PMID:34555281<ref>PMID:34555281</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 6g5x" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Jumonji domain-containing protein 3D structures|Jumonji domain-containing protein 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Carter DM]]
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[[Category: Gohlke U]]
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[[Category: Heinemann U]]
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[[Category: Malecki PH]]
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[[Category: Nazare M]]
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[[Category: Specker E]]
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[[Category: Weiss MS]]

Current revision

Crystal Structure of KDM4A with compound YP-02-145

PDB ID 6g5x

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